ACCOUNT
21
Application of Organic Azides for the Synthesis of Nitrogen-Containing
Molecules
Shunsuke Chiba*
Abstract: In this account, recent advances made on the reactions of
several types of organic azides, such as vinyl azides, cyclic 2-azido
alcohols, a-azido carbonyl compounds, towards the synthesis of
nitrogen-containing molecules are described.
1
2
2.1
2.2
2.3
2.4
3
3.1
3.2
4
4.1
4.2
4.3
5
Introduction
Chemistry of Vinyl Azides
Thermal [3+2]-Annulation of Vinyl Azides with 1,3-Dicarbonyl Compounds
Manganese(III)-Catalyzed Formal [3+2]-Annulation with
1,3-Dicarbonyl Compounds
Manganese(III)-Mediated/Catalyzed Formal [3+3]-Annulation with Cyclopropanols
Synthesis of Isoquinolines from a-Aryl-Substituted Vinyl
Azides and Internal Alkynes by Rhodium–Copper Bimetallic Cooperation
Chemistry of Cyclic 2-Azido Alcohols
Manganese(III)-Catalyzed Ring Expansion of 2-Azidocyclobutanols
Palladium(II)-Catalyzed Ring Expansion of Cyclic 2-Azido
Alcohols
Chemistry of a-Azido Carbonyl Compounds
Orthogonal Synthesis of Isoindole and Isoquinoline Derivatives
Generation of Iminylcopper Species and Their Catalytic
Carbon–Carbon Bond Cleavage under an Oxygen Atmosphere
Copper(II)-Catalyzed Aerobic Synthesis of Azaspirocyclohexadienones
Conclusion
Key words: azides, nitrogen-containing heterocycles, radical reactions, redox reactions, oxygenations
Organic azides possess diverse chemical reactivities.4
Owing to their 1,3-dipole character, they undergo [3+2]
cycloaddition with unsaturated bonds, such as those in
alkynes and alkenes as well as carbonitriles (Scheme 1,
part a).5 Organic azides can also be regarded as nitrene
equivalents (Scheme 1, part b).6 Accordingly, their reactions with nucleophilic anions, electrophilic cations, and
radicals can formally provide the corresponding nitrogen
anions, cations, and radicals, respectively, forming a new
bond with the internal azido nitrogen and releasing molecular nitrogen. Moreover, the generation of anions, cations,
and radicals at the a-position to the azido moiety can result in rapid denitrogenation to deliver the corresponding
iminyl species, which can be used in further synthetic
transformations (i.e., carbon–nitrogen bond formation).
(a) 1,3-Dipoles
R N N N
C C
triazolines
C C alkenes
R N N N
+
C C alkynes
C N
R N N N
R N N N
C N
tetrazoles
nitriles
R N N N
C C
triazoles
(b) Nitrene equivalents
R N N N
R N
nitrenes
+
N2
with carbanions or other nucleophiles
R N N N
+
X–
R N X
+
N2
C+
R N C
+
N2
C
R N C
+
N2
with carbocations
R N N N
+
with carbon radicals
R N N N
1
Introduction
The chemistry of organic azides commenced with the synthesis of phenyl azide by Griess in 18641 and the discovery of the rearrangement of acyl compounds with
hydrogen azide (HN3) by Curtius in 1890.2 Since 1950,
various synthetic organic reactions have been developed
using acyl, aryl, and alkyl azides, which have been extensively applied for the synthesis of nitrogen-containing
azaheterocycles as well as peptides.3
SYNLETT 2012, 23, 21–44xx. 201
Advanced online publication: 09.12.2011
DOI: 10.1055/s-0031-1290108; Art ID: A59911ST
© Georg Thieme Verlag Stuttgart · New York
+
chemistry of α-azido anions, cations, and radicals
C N N N
C N
+
N2
C N N N
C N
+
N2
C N N N
C N
+
N2
Scheme 1
We have been interested in the intriguing chemical reactivity of organic azides, such as vinyl azides, cyclic 2-azido alcohols, and a-azido carbonyl compounds
(Scheme 2). In this account, we describe recent advances
made on the reactions of these organic azides towards the
synthesis of nitrogen-containing molecules which have
been developed in our research group.
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Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
Fax +6567911961; E-mail: [email protected]
Received 31 May 2012
ACCOUNT
S. Chiba
N
N
N
HO
R'
R
vinyl azides
inyl species serve for the formation of carbon–nitrogen
bonds. In this section, we present the synthesis of azaheterocycles from vinyl azides via several types of reaction
mode based on the above chemical reactivities.
N
N
N
N
N
N
R
cyclic 2-azido
alcohols
O
a-azido carbonyl
compounds
2.1
Scheme 2
2
Chemistry of Vinyl Azides
Intermolecular annulation reactions can allow for the
straightforward and selective construction of complex cyclic molecular structures in a one-pot manner from relatively simple building blocks, one of the most ideal
processes in organic synthesis from an atom-7 and stepeconomical8 point of view. Inspired by this perspective,
we have recently been interested in the application of vinyl azides as a three-atom unit including one nitrogen for
various types of annulation reactions to prepare azaheterocycles.
One of the attractive chemical properties of vinyl azides is
their ability to undergo thermal decomposition to give
highly strained three-membered cyclic imines, 2H-azirines, via vinylnitrene intermediates following denitrogenation (Scheme 3, part a).9 Moreover, the carbon–carbon
double bond of vinyl azides can be used for the formation
of new carbon–carbon bonds with appropriate organometallic compounds (R′–[M]) or radical species (R¢) which
results in the generation of iminyl metals or iminyl radicals, respectively (Scheme 3, parts b and c).10 These imR
Δ
– N2
N
N
N
R
vinylnitrenes
R
R'–[M]
N
N
N
R
N
N
N
R
N
R'
R'
R
[M] N
N
N
R'
(a)
N
2H-azirines
R
R'
(b)
N
[M]
– N2
R
N
N
N
– N2
R
R'
(c)
N
Scheme 3
Thermal [3+2]-Annulation of Vinyl Azides
with 1,3-Dicarbonyl Compounds
During the course of our study on the chemistry of 2Hazirine derivatives,11 it was found that the reaction of azirine 1 with acetylacetone (2) in 1,2-dichloroethane at room
temperature gave tetrasubstituted pyrrole 3 in quantitative
yield after 33 hours (Scheme 4).
EtO2C
Cl
Cl
N
Cl
1
CO2Et O
+
Me
O
N
H
Me
DCE
2 (1.2 equiv) r.t., 33 h
COMe
Me
Cl
3 quant
Scheme 4
While the reaction of azirine 1 with acetylacetone (2) in
tetrahydrofuran (THF) has been reported, the yield of pyrrole 3 was low.12 The generation of 3 in high yield in the
above reaction (Scheme 4) led us to further investigate the
pyrrole formation.
The reaction may proceed through the addition of acetylacetone (2) to the imino carbon of azirine 1,13 followed by
nucleophilic attack of the nitrogen in the resulting aziridine to a carbonyl group with concurrent ring opening of
the strained three-membered ring.14 However, the instability and poor accessibility of the 2H-azirines prevented
us using this strategy as a synthetic method for pyrroles.
Accordingly, we planned to use vinyl azides as precursors
of 2H-azirines which can be easily synthesized15 and handled (Scheme 5).
As proposed in Scheme 5, simple heating of a mixture of
ethyl 2-azido-3-(2,6-dichlorophenyl)acrylate (4) and
acetylacetone (2) in toluene at 100 °C provided pyrrole 5
in 86% yield (Table 1, entry 1).16 Various 2-azido-substituted cinnamates possessing electron-donating and -withdrawing groups on the phenyl group (entries 2–8), as well
as a derivative containing a pyridyl moiety (entry 9), reacted with acetylacetone (2) to give the corresponding 2-
Biographical Sketch
Shunsuke Chiba was born
in Zushi, Kanagawa, Japan,
in 1978. He obtained his
B.Eng. from Waseda University in 2001 and received
his Ph.D. in 2006 from the
Synlett 2012, 23, 21–44
University of Tokyo (working under Professor Koichi
Narasaka). He was appointed as a research associate at
the University of Tokyo in
2005. In 2007, he moved to
Nanyang
Technological
University, Singapore, as an
assistant professor. His research focus is methodology
development in the area of
synthetic organic chemistry.
© Thieme Stuttgart · New York
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22
ACCOUNT
R2
O
+
N
N2
Δ
– N2
– H 2O
O
Me
Me
2
R2
R1
N
Me
N
H
– N2
R1
indoles via intramolecular C–H amination.17,18 It is noteworthy that the above intermolecular reactions of 2-azidosubstituted cinnamate derivatives with acetylacetone (2)
gave pyrroles exclusively without any indole formation.
COMe
– H 2O
R2
O
Me
R2
R1
HN
Me
H O
H
O
Me
Me
R2
O
A
R
1
As b-substituents (R1) of azidoacrylates, ethoxycarbonyl
and alkyl groups could be introduced, giving the corresponding pyrroles in good yields (entries 12 and 13). Simple azidoacrylate 30 also reacted smoothly (entry 14).
Using a-aryl-substituted vinyl azides, not only phenyl
groups, but also naphthyl, indolyl, pyrrolyl, and benzothiophenyl moieties could be installed at the 3-position
of the resulting trisubstituted pyrroles (entries 15–26). aAlkyl-substituted vinyl azide 56 reacted smoothly to give
the corresponding pyrrole 57 in 82% yield (entry 27). An
E,Z-mixture of 2-phenylvinyl azide (58) could also be
used to prepare trisubstituted pyrrole 59 in 85% yield (entry 28). Tetrasubstituted pyrroles 61 and 63 were success-
COMe
Me
N OH
H
B
Scheme 5
arylpyrroles in good yields. Vinyl azides 22 and 24 bearing acetyl and (dimethylamino)carbonyl moieties instead
of an a-ethoxycarbonyl group could be employed to give
the corresponding pyrroles 23 and 25 (entries 10 and 11,
respectively). It is known that the thermolysis of 2-azidosubstituted cinnamates and their derivatives delivers 1H-
Synthesis of Pyrroles from Vinyl Azides and Acetylacetone (2)a
Table 1
R2
R1
1
2
3
4
5
6
7
8c
4: R = 2,6-Cl2
6: R = H
8: R = 4-Me
CO2Et 10: R = 2-Me
12: R = 3-NO2
N3
14: R = 4-Br
16: R = 4-CN
18: R = 4-MeO
R
Δ
O
Me
Me
2
Pyrrolesb
Vinyl azides
Entry
O
+
N
N2
EtO2C
COMe
Me
N
H
R
5 86%
7 93%
9 90%
11 89%
13 96%
15 90%
17 90%
19 81%
R2
COMe
– N2
– H 2O
R1
Entry
Vinyl azides
Me
N
H
Pyrrolesb
O
24
50
N
Ts
N3
TsN
51 92%
Me
Me
N
H
O
EtO2C
CO2Et
9
R2
10d
11
N3
TsN
25
20
N3
N
COMe
Me
N
H
N
R2
22: R2 = COMe
24: R2 = CONMe2
21 94%
N3
N
Ts
53 92%
S
N
H
23 74%
25 quant
26
S
CO2Et
R1
N3
15
16
17
18
19
20
21
R
N3
26: R1 = CO2Et
28: R1 = CH2Ph
30: R1 = H
32: R = H
34: R = 4-Me
36: R = 4-OMe
38: R = 2-OMe
40: R = 4-Br
42: R = 3-Br
44: R = 4-CO2Me
EtO2C
R1
COMe
N
H
Me
R
COMe
N
H
Me
27 82%
29 96%
31 85%
33
35
37
39
41
43
45
75%
98%
95%
86%
92%
91%
86%
O
Me
54
O
Ph
Ph
27
Me
56
N3
55 96%
Me
N
H
N3
12
13e
14
Me
N
H
COMe
Me
Me
52
57 82%
Me
N
H
COMe
28
N3
58
(E:Z = 1:1)
59 85%
Me
N
H
O
Me
COMe
46
22
N3
N
H
47 94%
60
29
O
Me
COMe
48
23
N3
N
H
Me
49 65%
30
Me
62
N3
61 66%
Me
N
H
N3
Me
Me
N
H
63 91%
Me
a
Unless otherwise noted, the reactions were carried out by heating a mixture of the vinyl azide (0.3–0.5 mmol) and acetylacetone (2) (1.2 equiv)
in toluene at 100 °C for 2–24 h.
b
Isolated yields are shown.
c
The reaction was performed at 85 °C for 16 h.
d
The reaction was performed at 85 °C for 20 h in the presence of acetylacetone (2) (2 equiv).
e
The reaction was performed at reflux for 5 h.
© Thieme Stuttgart · New York
Synlett 2012, 23, 21–44
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R1
23
Applications of Organic Azides for the Synthesis of Nitrogen-Containing Molecules
ACCOUNT
S. Chiba
fully synthesized from a,b-disubstituted vinyl azides 60
and 62 (entries 29 and 30, respectively).
The scope of the reaction using different 1,3-dicarbonyl
compounds was next investigated with several vinyl
azides (Table 2).16 The reactions of 1,3-diketones bearing
terminal alkene moieties or phenyl groups, such as 64 or
68, respectively, with several vinyl azides resulted in the
formation of the corresponding pyrroles (entries 1–4). The
reactions of b-keto aldehyde 70 proceeded smoothly with
vinyl azides 6 and 26 forming tri- and tetrasubstituted pyrroles 70/71 and 73/74 in almost 1:1 ratios (entries 5 and 6,
respectively), probably via nucleophilic attack of the nitrogen atom to both carbonyl groups (see Scheme 5, A to
B). However, the treatment of vinyl azides 6 and 58 with
a b-keto ester, ethyl acetoacetate (75), resulted in sluggish
reactions, giving the desired pyrroles 76 and 77 in only 30
and 58% yield (entries 7 and 8, respectively) along with
complex mixtures.
Table 2 Scope of the Reaction Using Different 1,3-Dicarbonyl
Compoundsa
Entry
1,3-Dicarbonyl
compounds
Vinyl azides
Pyrrolesb
O
CO2Et
1
O
EtO2C
O
N3
Me
8
N
H
Me
64
EtO2C
CO2Et
EtO2C
2
64
N3
EtO2C
26
Our reaction design was based on the addition of a carbon
radical bearing a carbonyl group to the carbon–carbon
double bond of a vinyl azide to provide a new carbon–carbon bond with the generation of an iminyl radical. The iminyl radical would then intramolecularly form a carbon–
nitrogen bond with the carbonyl, resulting in cyclization
leading to various azaheterocycles (Scheme 6).19,20 The
proposed process could potentially be achieved in a redox
catalytic manner featuring two key redox steps: (1) oxidative generation of the radical species by the reaction of
radical sources with a metal oxidant [Mn] (to become
[Mn–1]) (oxidative initiation) and (2) reduction of the resulting iminyl radical by [Mn–1] and its cyclization with
the intramolecular carbonyl group to give azaheterocycles
and regenerate [Mn] (reductive termination).
radical
sources
oxidative initiation
[Mn-1]
R
N
N
N
R
[Mn]
C
N C
OH
H+
R
C
azaheterocycles
C
N C
66 94%
64
3
N3
N
H
32
O
4
67 80%
O
O
32
N
H
Manganese(III)-Catalyzed Formal [3+2]Annulation with 1,3-Dicarbonyl Compounds
Besides the above-mentioned thermal [3+2]-annulation of
vinyl azides and 1,3-dicarbonyl compounds, we planned
to use the carbon–carbon double bond of vinyl azides for
the formation of a new carbon–carbon bond to initiate another type of annulation reaction.
N
H
O
68
2.2
65 90%
O
69 95%
O
EtO2C
O
CO2Et
5
N
H
O
H
N3
6
71 54%
EtO2C + CHO
70
N
H
72 43%
O
EtO2C
EtO2C
N
H
73 41%
EtO2C + CHO
CO2Et
EtO2C
6
70
N3
26
EtO2C
N
H
74 39%
O
CO2Et
7
N3
O
OEt
Me
75
6
EtO2C
O
OEt
Me
N
H
76 30%
O
OEt
8
N3
58
75
N
H
Me
77 58%
a
The reactions were carried out by heating a mixture of the vinyl
azide (0.3–0.5 mmol) and 1,3-dicarbonyl compound (1.2 equiv) in
toluene at 100 °C for 2–24 h.
b
Isolated yields are shown.
O[Mn]
C
O
R
N2
C
N
R
C
N
C
O [Mn-1]
Scheme 6
Synlett 2012, 23, 21–44
C
[Mn] O
reductive termination
Based on this concept, manganese(III) acetate, which has
been extensively used for oxidative radical reactions using carbonyl compounds,21 was employed in the reaction
of 1-phenylvinyl azide (32) and ethyl acetoacetate (75) in
methanol (MeOH) under a nitrogen atmosphere. As expected, the reaction proceeded smoothly at 40 °C using 10
mol% of manganese(III) acetate in the presence of acetic
acid (AcOH), affording trisubstituted pyrrole 77 in 94%
yield (Scheme 7). This catalytic reaction is initiated by the
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24
ACCOUNT
addition of manganese(III) enolate I to vinyl azide 32 in
the radical pathway, giving iminyl radical II with the release of a manganese(II) [Mn(II)] species and molecular
nitrogen. The reaction of iminyl radical II with the Mn(II)
species affords iminylmanganese(III) [(alkylideneamino)manganese(III)] III, the nucleophilic attack of which
to a carbonyl group yields cycloaddition intermediate IV.
Finally, protonation of IV with AcOH followed by dehydration yields pyrrole 77 along with regeneration of
Mn(III).
O
+
77 94%
75
EtO
O
Me
O
75
O
Ph
Vinyl azides
[MnIII]/mol%
O
N
N
N 32
AcOH
Me
[MnII], N2
I
EtO
O
MnIII(OAc)3
Ph
O
N
EtO
AcOH
Ph
CO2Et
Ph
Me
N OH
[MnII]
O
Ph
N O
[MnIII]
II
O
CO2Et
Me
N
[MnIII]
IV
III
H2O
77
Scheme 7
+
R2
OEt
Me
R2
cat. Mn(OAc)3⋅2H2O
O
R1
MeOH, 40 °C
75
Product (yield/%)b
Time/h
R
Entry
Vinyl azides
CO2Et
Me
N
H
[MnIII]/mol%
R
32: R = H
78: R = 2-Br
40: R = 4-Br
44: R = 4-CO2Me
82: R = 3-NO2
34: R = 4-Me
38: R = 2-OMe
CO2Et
10
10
10
10
10
10
10
13
Me
N
H
8
20
46
93 (85)
CO2Et
RO
N
H
87 (72)
94: R = Ac
20
1
95 (94)
96: R = Si(t-Bu)Ph2
20
2
97 (85)
40
1
CO2Et
Me
16
98 (60)d
60
Me
52
20
OAc
40
5
O
N3
N
N
Ts
H
88 (68)c
H
N
EtO2C
Me
18
N3
24
Me
N3
99
Me
EtO2C
40
11
N
H
19
20
56
N3
3
91 (90)
N
H
2
t-Bu
100 (74)
CO2Et
EtO2C
Me
N
H
101 (98)
N3
Me
Me
N
H
O
EtO2C
CO2Et
12
5
Si
30
CO2Et
90 (48)
89
t-Bu
N3
24
N3
CO2Et
OAc
O
Si
t-Bu O
t-Bu
17
Me
N
H
N3
CO2Et
N
Me
N
H
15
2
N3
62
N3
14
86 (83)
Me
CO2Et
20
Me
N
H
N3
N
H
Me
9
O
2
RO
2
N3
20
O
92
77 (94)
79 (94)
80 (86)
81 (88)
83 (95)
84 (78)
85 (75)
2
2
2
2
2
4
4
CO2Et
Ts
Products (yield/%)b
Time/h
CO2Et
N3
10
[MnIII]
O
OEt
20
CO2Et
24
EtO2C
6
Me
N
H
102 (78)e
a
Reactions were performed in MeOH at 40 °C with 1.5 equiv of ethyl acetoacetate (75) under a N2 atmosphere.
Isolated yields are shown.
c
Vinyl azide 52 was recovered in 25% yield.
d
Vinyl azide 60 was recovered in 10% yield.
e
Vinyl azide 6 was recovered in 15% yield.
b
© Thieme Stuttgart · New York
Synlett 2012, 23, 21–44
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N
N2
1
2
3
4
5
6
7
Me
N
H
MeOH, 40 °C, 2 h
Manganese Acetate Catalyzed Reaction of Vinyl Azides with Ethyl Acetoacetate (75)a
R1
Entry
CO2Et
Mn(OAc)3⋅2H2O (10 mol%)
AcOH (2 equiv)
O
Me
OEt
(1.5 equiv)
N
N2
32
The scope of this catalytic pyrrole formation was found to
be quite broad. A series of vinyl azides could be employed
with ethyl acetoacetate (75), as shown in Table 3.19b aAryl-substituted vinyl azides reacted smoothly to afford
the corresponding pyrroles in good yields (entries 1–9).
Tetrasubstituted pyrrole 87 could be synthesized from 2methyl-1-phenylvinyl azide (62) in good yield (entry 9).
The reaction of 2-pyrrolylvinyl azide 52 gave bipyrrole 88
in 68% yield (entry 10). 1,4-Dipyrroylbenzene 90 could
be obtained by treatment of 1,4-bis(1-azidovinyl)benzene
Table 3
25
Applications of Organic Azides for the Synthesis of Nitrogen-Containing Molecules
ACCOUNT
S. Chiba
(89) with 40 mol% of manganese(III) acetate, although
the yield was moderate (entry 11). a-Alkyl-substituted vinyl azides could also be used for this pyrrole formation,
giving the corresponding pyrroles in good yields (entries
12–17). Bicyclic pyrrole 98 was obtained in 60% yield
from 1-azidocyclooctene (60) (entry 16). Vinyl azide 99
bearing a chiral polyol functionality22 could be converted
into pyrrole 100 in 74% yield (entry 17). Azidoacrylates
could also be employed in the above catalytic process (entries 18 and 19). While the reaction of ethyl 2-azidoacrylate (30) needed only 5 mol% of manganese(III) acetate to
complete within 2 hours, affording pyrrole 101 almost
quantitatively (entry 18), that of 2-phenylvinyl azide 6 required a longer reaction time (24 h), probably owing to
steric hindrance (entry 19).
Next, the generality of this reaction using different b-keto
esters was examined with 1-phenylvinyl azide (32) and
ethyl 2-azidoacrylate (30), as shown in Table 4.19b By
varying the substituent on the b-keto ester through the use
of 103–105, phenyl, ethoxymethyl, and cyclopropyl
groups could be successfully installed at the C-2 position
of the resulting pyrrole to give products 106–111.
Table 4 Manganese Acetate Catalyzed Synthesis of Pyrroles from
Vinyl Azides and 1,3-Dicarbonyl Compoundsa,b
CO2Et
N
32
N2 or
+
EtO2C
N
N2
O
O
Table 5 Reactions of Vinyl Azides with 1,3-Diketones Catalyzed
by Manganese(III) Tris(pyridine-2-carboxylate)a,b
N
Mn
R
R
2
O
+
N
H
3
O
(20 mol%)
R2
R4
2
O
R3
AcOH (2 equiv)
R1
MeOH, 40 °C
(1.5 equiv)
1,3-diketones:
O O
Me
O
R3
N
N2
O
O
R4
N
H
O
Me
Me
112
113
Me
COMe
COMe
COMe
AcO
R
N
H
CO2Et
EtO2C
O
O
1
R
or
MeOH, 40 °C
OEt
R
(1.5 equiv)
30
β-keto esters:
O
N
H
cat. Mn(OAc)3•2H2O
AcOH (2 equiv)
afforded pyrrole 114 in 76% yield after 20 hours
(Table 5).19b Treatment of other vinyl azides with acetylacetone (2) using 20 mol% of Mn(pic)3 led to the formation of pyrroles 115–118 in moderate to good yields,
whereas electron-deficient vinyl azide 30 delivered the
desired pyrrole 119 in only 28% yield along with a complex mixture. The reaction of 1,3-diphenylpropane-1,3dione (112) with vinyl azide 32 gave a moderate yield of
pyrrole 120, probably owing to the steric hindrance of the
benzoyl group. The reaction of unsymmetrical 1,3-diketone benzoylacetone (113) with vinyl azides proceeded to
afford pyrroles 121–123 in moderate to good yields as the
sole products via carbon–nitrogen bond formation with
the less-hindered acetyl group.
R
Me
N
H
114: R = H; 76% (32+2)
115: R = 3-NO2; 80% (82+2)
116: R = 4-Me; 52% (34+2)
Me
117: 41% (62+2)
O
N
H
Me
118: 71% (94+2)
O
COMe
O
O
OEt
103
O
O
EtO
O
OEt
OEt
104
CO2Et
EtO2C
105
N
H
Me
119: 28% (30+2)
CO2Et
CO2Et
N
H
120: 32% (32+112)c
Me
N
H
R
121: R = H; 61% (32+113)
122: R = 4-Br; 55% (40+113)
123: R = 4-CO2Me; 85% (44+113)
OEt
N
H
N
H
N
H
106: 63% (32+103)
108: 55% (32+104)
CO2Et
CO2Et
EtO2C
N
H
107: 72% (30+103)
OEt
N
H
109: 77% (30+104)
EtO2C
110: 56% (32+105)
CO2Et
EtO2C
N
H
111: 72% (30+105)
a
Reactions were performed in MeOH at 40 °C with 1.5 equiv of the
1,3-dicarbonyl compound under a N2 atmosphere.
b
Isolated yields are shown next to the corresponding products.
The reaction of acetylacetone (2) instead of b-keto esters
with vinyl azide 32 in the presence of 20 mol% of manganese(III) acetate was sluggish, and pyrrole 114 was obtained in low yield (21%) along with the recovery of vinyl
azide 32 (63%), even after 24 hours. To improve the product yield in the reaction with acetylacetone (2), other
Mn(III) complexes were screened. Although manganese(III) acetylacetonate [Mn(acac)3] displayed no catalytic activity in this reaction, the use of 20 mol% of
manganese(III) tris(pyridine-2-carboxylate) [Mn(pic)3]23
Synlett 2012, 23, 21–44
a
Reactions were performed with 0.3 mmol of the vinyl azide under a
N2 atmosphere.
b
Isolated yields are shown next to the corresponding products.
c
Vinyl azide 32 was recovered in 27% yield.
b-Keto acids have been used as either a-carbonyl anion24
or radical25 equivalents with the elimination of carbon dioxide. Our findings on the reactivity of vinyl azides towards the a-carbonyl radicals derived from b-keto esters
and 1,3-diketones with Mn(III) catalysts drove us to examine the reaction of vinyl azides and b-keto acids. In this
case, Mn(acac)3 suitably catalyzed the reaction to synthesize the corresponding substituted pyrroles.
The reactions of various vinyl azides with b-keto acid 124
are summarized in Table 6.19a The reaction of a-aryl-substituted vinyl azides with 124 provided the desired bicyclic pyrroles in good yields (entries 1–6). Notably, the
reaction of vinyl azide 50 bearing an a-indol-2-yl substituent resulted in the formation of 2,2¢-biindole derivative
130 (entry 6). 2-Azidoacrylate derivatives 30 and 26
© Thieme Stuttgart · New York
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26
could also be used, giving the corresponding bicyclic pyrroles 131 and 132 in good yields (entries 7 and 8, respectively). In the case of vinyl azide 26, the presence of an
ethoxycarbonyl group at the b-position did not retard the
process, which gave tetrasubstituted pyrrole 132 in 74%
yield (entry 8).
Scope of the Reaction Using Different b-Keto Acidsa
Table 7
O
+
O
124
(1.5–3 equiv)
Entry
N3
Pyrroles
50
N
Ts
N3
EtO2C
30
N3
8
EtO2C
CO2Et
N
H
N
Ts
EtO2C
EtO2C
O
OH
O
Me
OH
141: R = Et
143: R = Ph
O
145
Me
O
131: 68c
132: 74c
N
H
Reactions were performed in DMF at r.t. with 1.5–3.0 equiv of bketo acid 124 under a N2 atmosphere.
b
Isolated yields are shown.
c
10 mol% of Mn(acac)3 was used.
d
20 mol% of Mn(acac)3 was used.
The scope of the b-keto acids in the reaction was next investigated with vinyl azide 32 (Table 7).19a Tetrahydropyrano[4,3-b]pyrrole
134
and
4,5-dihydro-1Hbenzo[g]indole 136 were constructed in good yields by
employing b-keto acids 133 and 135 (entries 1 and 2, respectively). Bicyclic pyrroles 138 and 140 bearing larger
carbocycles could also be synthesized in good yields (entries 3 and 4, respectively). In addition, linear b-keto acids
141 and 143 could be employed, affording the trisubstituted pyrroles 142 and 144 in good yields (entries 5 and 6,
respectively). However, b-keto acid 145, the precursor of
a primary a-carbonyl radical, was not a viable substrate,
giving only low yields of the desired pyrrole 146 even
when using stoichiometric amounts of different Mn(III)
complexes (entry 7).
146: 23f
N
H
a
Reactions were performed in DMF at r.t. with 1.5–3.0 equiv of the
b-keto acid under a N2 atmosphere.
b
Isolated yields are shown.
c
30 mol% of Mn(acac)3 was used.
d
40 mol% of Mn(acac)3 was used and b-keto acid 135 was added via
a syringe pump over 1 h.
e
20 mol% of Mn(acac)3 was used.
f
Mn(pic)3 (1 equiv) was used; the use of Mn(acac)3 (1 equiv) afforded
pyrrole 146 in only 10% yield.
nylpyridine (148) was investigated. The possible reaction
pathway is depicted in Scheme 8. The reaction is initiated
by the addition of b-carbonyl radical I, generated via the
one-electron oxidation of cyclopropanol 147 using the
metal oxidant [Mn], to vinyl azide 32, affording iminyl
radical II with the elimination of molecular nitrogen. The
reaction of iminyl radical II with [Mn–1] affords iminylmetal species III, and its intramolecular nucleophilic attack to the carbonyl group gives cyclized intermediate IV.
Subsequent protonation affords tetrahydropyridine V
HO Ph
[Mn-1], H+
O
Ph – H O
2
Ph
OH
N
V
Ph
[Mn]
147
Ph
© Thieme Stuttgart · New York
N
N
N
Ph
N
148
Ph
O
Ph
Ph
Ph
N
[Mn]
III
O
32
N2
Ph
Ph
O [Mn]
N
IV
O
I
N
VI
[O]
H+
Ph
Ph
The reaction of 1-phenylvinyl azide (32) and 1-phenylcyclopropanol (147) to give the target compound 2,6-diphe-
142: 84e
144: 82e
R
N
H
Manganese(III)-Mediated/Catalyzed Formal
[3+3]-Annulation with Cyclopropanols
We next focused on the use of cyclopropanols as precursors of b-carbonyl radicals and investigated their addition
reactions with vinyl azides followed by carbon–nitrogen
bond formation (formal [3+3]-annulation).26
138: 81e
140: 82e
n
N
H
OH
N
H
136: 65d
N
H
O
R
7
135
137: n = 1
139: n = 2
n
5
6
134: 70c
N
H
O
3
4
125: 83c
126: 92d
127: 68d
128: 91d
129: 87d
a
2.3
133
OH
O
N
H
EtO2C
O
2
Yield/%b
Yield/%b
O
O
N
H
R1
N
H
DMF, r.t.
Pyrroles
OH
130: 78c
26
N3
O
O
R1
DMF, r.t.
32: R = H
40: R = 4-Br
44: R = 4-CO2Me
R
38: R = 2-MeO
36: R = 4-MeO
R
R2
(1.5–3 equiv)
1
R2
cat. Mn(acac)3
Vinyl azides
6
7
OH
+
N
N2
1
2
3
4
5
O
R2
cat. Mn(acac)3
OH
β-Keto acids
Entry
R2
O
R1
N
N2 32
Table 6 Scope of the Reaction with a b-Keto Acid Using Different
Vinyl Azidesa
R1
27
Applications of Organic Azides for the Synthesis of Nitrogen-Containing Molecules
Ph
Ph
N
[Mn-1]
II
Scheme 8
Synlett 2012, 23, 21–44
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ACCOUNT
ACCOUNT
S. Chiba
along with regeneration of [Mn]. Dehydration of V and
subsequent oxidation result in the desired pyridine 148.
We commenced our study on the pyridine formation using
a stoichiometric amount of a Mn(III) complex for the oxidation of cyclopropanol 14727 as well as dihydropyridine
VI (Scheme 8). It was found that the treatment of a mixture of vinyl azide 32 and cyclopropanol 147 (1.5 equiv)
with 1.7 equivalents of Mn(acac)3 in MeOH led to the rapid consumption of vinyl azide 32 within 5 minutes at room
temperature. Stirring for a further 1 hour after the addition
of AcOH (2 equiv) afforded 2,6-diphenylpyridine (148) in
84% yield (Scheme 9, part a). It was noted that other metal oxidants, such as silver(I),28 iron(III),29 or copper(II)30
complexes, were not viable for this transformation.
Next, we intended to use a catalytic amount of Mn(acac)3
with another stoichiometric oxidant for the aromatization
of dihydropyridine VI to give 148 (Scheme 8). It was revealed that the treatment of a mixture of vinyl azide 32
and cyclopropanol 147 with a catalytic amount of
Mn(acac)3 (10 mol%) in MeOH also led to the consumption of vinyl azide 32 within 5 minutes at room temperature. The subsequent addition of oxygen (under O2, 1 atm)
and hydrogen chloride (HCl) (2 equiv) provided the desired pyridine 148 in 80% yield (Scheme 9, part b).
Mn(acac)3
(1.7 equiv)
HO
+
N
N2
147
(1.5 equiv)
AcOH
(2 equiv)
MeOH, r.t., 5 min
under N2
terestingly, the corresponding reactions with Mn(pic)3 in
acetonitrile provided 2,3,6-trisubstituted pyridines 159–
161 in moderate yields. This was probably due to the low
solubility of Mn(pic)3 in acetonitrile that would allow
only a low concentration of the generated b-carbonyl radical so as to prevent its side reactions.
Next, the catalytic pyridine formation (using conditions
B) was examined for the synthesis of pyridines 148, 150,
155, and 157. The yields of the corresponding pyridines
are shown in parenthesis in Table 8 and are almost comparable with those obtained under the stoichiometric conditions.
Table 8 Manganese(III)-Mediated Pyridine Formation from Vinyl
Azides and Cyclopropanol 147a,b
R1
R2
N
N2
+
HO
147
(1.5 equiv)
N
R
conditions A:
Mn(acac)3 (1.7 equiv), r.t., 5 min
then AcOH (2.0 equiv), r.t. / MeOH
R2
R1 N
conditions B:
Mn(acac)3 (10 mol%), r.t., 5 min
then HCl (2.0 equiv) under O2, 40 °C / MeOH
148: R = H
149: R = 4-Me
150: R = 2-OMe
151: R = 4-OMe
152: R = 2-Br
153: R = 4-Br
154: R = 4-CO2Me
84% (80%)
84%
71% (70%)
70%
47%c
70%
70%
N
155 75% (72%)
R2
N
(a)
148 84%
N
N
EtO2C
N
Ts
N
Ts
156 70%d
157 66% (50%)d
32
N
158: R2 = H 51%
159: R2 = Ph 30%e
Me
Mn(acac)3
(10 mol%)
32
+
147
(1.5 equiv)
MeOH, r.t., 5 min
under N2
HCl
(2 equiv)
under O2
148 80%
Scheme 9 Optimized reaction conditions for pyridine formation
using a vinyl azide and a cyclopropanol
Using Mn(acac)3 in both a stoichiometric and aerobic catalytic manner, the generality of this Mn(III)-mediated/catalyzed pyridine formation was investigated with various
vinyl azides (Table 8).26
By applying the stoichiometric use of Mn(acac)3 (conditions A), the reactions of a range of a-aryl-substituted vinyl azides with cyclopropanol 147 afforded 2,6diarylpyridines in moderate to good yields. Heteroaryl
motifs, such as pyrrolyl and indolyl groups, were successfully incorporated into the product, as shown in the formation of 156 and 157. The reaction of electron-deficient
azidoacrylate 30 provided pyridine 158 in 51% yield.
When the reactions of a,b-disubstituted vinyl azides 6, 62,
and 60 were performed using Mn(acac)3 in MeOH, the
generated b-carbonyl radical underwent self-coupling or
hydrogen abstraction preferentially, leading to the desired
pyridines in only trace amounts. This indicated that the
addition of the b-carbonyl radical to the a,b-disubstituted
vinyl azides was extremely slow owing to the steric hindrance of the b-substituents on the latter compounds. InSynlett 2012, 23, 21–44
N
N
160 45%e
161 52%e
(b)
a
Unless otherwise noted, the reactions were carried out under either
conditions A or B; A: treatment of a mixture of the vinyl azide (0.3
mmol) and cyclopropanol 147 (1.5 equiv) with Mn(acac)3 (1.7 equiv)
in MeOH at r.t. under a N2 atmosphere for 5 min, followed by the addition of AcOH (2 equiv); B: treatment of a mixture of the vinyl azide
(0.3 mmol) and cyclopropanol 147 (1.5 equiv) with Mn(acac)3 (0.1
equiv) in MeOH at r.t. under a N2 atmosphere for 5 min, followed by
the addition of HCl in MeOH (3 M, 2 equiv) with an O2 balloon (1
atm).
b
Isolated yields are shown next to the corresponding products. The
yields obtained under conditions B are shown in parenthesis.
c
Vinyl azide 78 was recovered in 30% yield.
d
A solution of cyclopropanol 147 and AcOH in MeOH was added to
the vinyl azide and Mn(acac)3 via a syringe pump over 1 h.
e
The reactions were run using Mn(pic)3 (1.7 equiv) and AcOH (2
equiv) in MeCN at 40 °C at r.t.
The scope of the cyclopropanols in the reaction was then
investigated with 1-phenylvinyl azide (32) under both the
stoichiometric and catalytic reaction conditions (conditions A and B, respectively), as shown in Table 9.26 1Arylcyclopropanols were converted into the corresponding 2,6-diarylpyridines in good yields (entries 1–3).
Moreover, some alkyl groups (entries 4–7) including
strained cycloalkyls, as in substrates 170 and 172, and a
piperidine moiety, as in compound 174, could be installed
© Thieme Stuttgart · New York
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28
at C-2 of the pyridine ring. The introduction of alkenyl
and alkynyl groups on the pyridine ring was a particular
feature of this method (entries 8 and 9, respectively). The
method also allowed for the installation of an alkoxycarbonyl group as well as a dimethyl(phenyl)silyl moiety
(entries 10 and 11, respectively). The reactions of vinyl
azide 32 and 1,2-disubstituted cyclopropanols 184 and
186 with Mn(pic)3 afforded 2,4,6-trisubstituted pyridines
185 and 187 (entries 12 and 13, respectively). In these
cases, secondary b-carbonyl radicals were found to be
formed predominantly via the oxidative ring opening of
184 and 186, judging from the substitution patterns of the
products.
The catalytic reaction (conditions B) provided almost
comparable results for most of the substrates, except in the
reactions to give pyridines 175 (entry 7) and 179 (entry 9).
We planned to broaden the reaction scope of this Mn(III)mediated pyridine synthesis using other types of cyclopropanols. The one-electron oxidation of 1-alkoxycyclopropanols should generate b-alkoxycarbonyl radicals,
which we also expected to add to vinyl azides. The reaction of vinyl azide 32 and 1-(ethyloxy)cyclopropanol
(188) proceeded smoothly and rapidly (within 5 min) using 10 mol% of Mn(acac)3 in ethanol (EtOH) at room temperature to result in the formation of d-keto ester 189 in
very high yield (Scheme 10). In this case, the generated
iminyl radical A was reduced by the resulting Mn(II) species to afford iminylmanganese(III) B, which could not
undergo intramolecular cyclization with the ethoxycarbonyl group, but was protonated to give imine C with regeneration of the Mn(III) species. Hydrolysis of imine C
during the workup process delivered d-keto ester 189.
Table 9 Manganese(III)-Mediated Pyridine Formation from Vinyl
Azide 32 and Cyclopropanolsa
+
N
N2 32
Entry
HO
R1
N
Mn(acac)3 (10 mol%)
OEt
+
Cyclopropanols
Yield/%b
Pyridines
Condition A
N
N2 32
188
(1.2 equiv)
O
N
1
2
3
162: R = 2-Br
164: R = 4-Br
166: R = 4-Ph
4
HO
168
5
HO
170
R
163
165
167
70
81
66
82
N
80
70
73
70
78
70
82
45
54
51
55
21
169
N
171
6
HO
N
172
173
7
8
HO
N
Bn
174
HO
Bn
N
N
175
N
176
177
N
9
HO
N
10
11c
180: R3 = CO2Me
182: R3 = SiMe2Ph
O
Mn(III)
OEt
N
R4
12c
Ph
O
OEt
O
Mn(II)
OEt
N
N
N
32
N
33
45
HO
– Mn(II), H+
188
181
183
R3
R4
• A proposed reaction mechanism
OEt
179
R3
O
189 96%
Condition B
R
HO
OEt
EtOH, r.t., 5 min
under N2
R2
conditions B:
R2 Mn(acac)3 (10 mol%), r.t., 5 min
(1.5 equiv) then HCl (2.0 equiv) under O , 40 °C / MeOH
2
178
HO
R1
conditions A:
Mn(acac)3 (1.7 equiv), r.t., 5 min
then AcOH (2.0 equiv), r.t. / MeOH
HO
HO
29
Applications of Organic Azides for the Synthesis of Nitrogen-Containing Molecules
O
A
H+
[Mn(III)]
OEt
NH
O
H2 O
189
(workup)
C
B
Scheme 10
To keep the nitrogen atom of the putative imine C in the
final product, we tried to reduce imine C to give an amine,
which would then undergo lactamization to provide a dlactam.31,32 After the consumption of vinyl azide 32 in the
reaction with cyclopropanol 188, sodium borohydride (2
© Thieme Stuttgart · New York
184:
= Me
186: R4 = Ph
185
187
63
40
OEt
N
– Mn(III)
13c
R4
a
Unless otherwise noted, the reactions were carried out under either
conditions A or B; A: treatment of a mixture of vinyl azide 32 (0.3
mmol) and the cyclopropanol (1.5 equiv) with Mn(acac)3 (1.7 equiv)
in MeOH at r.t. under a N2 atmosphere for 5 min, followed by the addition of AcOH (2 equiv); B: treatment of a mixture of vinyl azide 32
(0.3 mmol) and the cyclopropanol (1.5 equiv) with Mn(acac)3 (0.1
equiv) in MeOH at r.t. under a N2 atmosphere for 5 min, followed by
the addition of HCl in MeOH (3 M, 2 equiv) with an O2 balloon (1 atm).
b
Isolated yields.
c
The reaction was run using Mn(pic)3 (1.7 equiv) in MeCN at r.t.
equiv) was added to the reaction mixture, which provided
d-lactam 190 in 85% yield as expected (Scheme 11). A series of a-aryl-substituted vinyl azides possessing both
electron-withdrawing and electron-donating groups were
Synlett 2012, 23, 21–44
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ACCOUNT
ACCOUNT
S. Chiba
HO
R
Mn(acac)3 (10 mol%)
OEt
+
N
N2
R
OEt
EtOH, r.t., 5 min
under N2
188
(1.2 equiv)
NH
NaBH4
(2 equiv)
N
H
R
O
O
190: R = H; 85%
191: R = 4-Br; 80%
192: R = 4-CO2Me; 69%
193: R = 4-Me; 81%
194: R = 4-OMe; 87%
Scheme 11
transformed into aryl-substituted d-lactams 191–194 in
good yields.26a
Next, we envisaged using bicyclic cyclopropanols, such
as bicyclo[3.1.0]hexan-1-ol (195), as sources of b-carbonyl radicals. Interestingly, the unusual product 2-azabicyclo[3.3.1]non-2-en-1-ol 196 was isolated in 89% yield on
the reaction of compound 195 with vinyl azide 32 using
only a catalytic amount of Mn(acac)3 (5 mol%); the slow
addition of 195 via a syringe pump to a mixture of vinyl
azide 32 and the catalyst over 1 hour was required to complete the reaction (Scheme 12).26 It is noteworthy that the
treatment of optically active cyclopropanol 195 (85%
ee)33 with vinyl azide 32 afforded racemic compound 196.
The lack of transmission of the chirality of cyclopropanol
195 to bicyclic product 196 suggests that the generation of
achiral ring-expanded b-carbonyl radical I34 from 195 followed by its radical addition to vinyl azide 32 is involved
in the reaction mechanism. The radical addition would
form iminylmanganese(III) II-eq and II-ax bearing an iminyl tether in an equatorial- and axial-like position, respectively. The conformational inversion of II-eq to II-ax
would be indispensable for achieving the further intramolecular cyclization of iminylmanganese II-ax with the
carbonyl group to give alkoxymanganese(III) species III,
which would protonate to afford 196.
Mn(acac)3 (5 mol%)
+
N
N2
The treatment of 196 with sodium cyanoborohydride
(NaBH3CN) in the presence of HCl induced the double
hydride reduction of the carbon–nitrogen double bond and
carbon–oxygen
bond,
affording
2-azabicyclo[3.3.1]nonane 216 stereoselectively in 70% yield
(Scheme 13).26a The first hydride attacked the carbon–
nitrogen double bond entirely from the less-hindered exoface to form hemiaminal I. Subsequent dehydration of I
gave the bridgehead iminium species II, which could be
reduced by one more hydride to afford product 216.
OH
N
H
H
196
196 89%
(0% ee)
• A proposed catalytic cycle
H
N
H
H
MeOH, r.t., 2 h
216 70%
• A proposed reaction pathway
195
196
[MnIII]
H+
196
O[MnIII]
H+
[MnII], H+
O
H
NaBH3CN (3.0 equiv)
HCl in MeOH (3 equiv)
N
Ph
MeOH, r.t., 1 h
(slow addition of 195
through a syringe pump)
195
(85% ee)
(1.2 equiv)
32
Having prepared the 2-azabicyclo[3.3.1]non-2-en-1-ols,
we then explored their transformation into 2-azabicyclo[3.3.1]nonane (morphan)27 or 2-azabicyclo[3.3.1]non2-ene frameworks, which are prevalent in several natural
alkaloids as well as biologically active molecules.35
OH
OH
Ph
With the Mn(III)-catalyzed method to construct a 2-azabicyclo[3.3.1]non-2-en-1-ol structure in hand, the substrate scope of the reaction was next investigated
(Table 10).26 A variety of 3-aryl-2-azabicyclo[3.3.1]non2-en-1-ols were prepared in good to excellent yields; pyrrolyl and indolyl moieties were successfully incorporated
into the corresponding products (entries 8 and 9, respectively). The steric hindrance in a,b-disubstituted vinyl
azide 62 made its reaction sluggish, giving the desired
compound 205 in only 28% yield along with the recovery
of 62 (68%), even in the presence of 40 mol% of the catalyst (entry 10). The introduction of substituents, such as
alkyl, vinyl, and phenyl groups, at C-4 of the bicyclic cyclopropanol did not retard the reaction and provided the
corresponding 2-azabicyclo[3.3.1]non-2-en-1-ols in high
yields and with good diastereoselectivity (exo-selective,
83:17 to 94:6) (entries 11–15). In these cases, the addition
of the b-carbonyl radicals to vinyl azide 32 in the carbon–
carbon bond formation occurred in an anti-selective manner with respect to the adjacent C-4 substituents to minimize 1,2-steric repulsion.
H–
H
OH
Ph
H
H
III
Ph
H
H
N
H
O
H
N
OH
H+
H
I
H
Ph
Ph
Ph
N
[Mn(III)]
N
H
N
H–
OH2
H
Ph
–H2O
H
N
216
H
II
II-eq
O
Ph
N
N
N
[MnII]
I
32
Scheme 12
Synlett 2012, 23, 21–44
O
N
Ph
N2
Scheme 13
H
[Mn(III)]
II-ax
A one-pot conversion could be achieved starting from vinyl azide 32 and cyclopropanol 195 using Mn(acac)3 as a
catalyst followed by treatment with NaBH3CN (3 equiv)
and HCl (3 equiv). Product 216 was formed in good yield
without the isolation of 2-azabicyclo[3.3.1]non-2-en-1-ol
© Thieme Stuttgart · New York
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30
ACCOUNT
Table 10 Manganese(III)-Catalyzed Synthesis of 2-Azabicyclo[3.3.1]non-2-en-1-olsa
Vinyl azides
Cyclopropanols
N
N2
32: R = H
34: R = 4-Me
38: R = 2-OMe
36: R = 4-OMe
78: R = 2-Br
40: R = 4-Br
44: R = 4-CO2Me
H
195
195
195
195
195
195
195
R1
H
H
N
R2
H
89c
95
88
93
70
83
75
196
197
198
199
200
201
202
H
N
R1
H
H
H
H
N
R2
H
H
220: R2 = CH(CH3)2
221: R2 = CH=CH2
222: R2 = CH2CH=CH2
223: R2 = Ph
70% (32+195)
216: R1 = H
217: R1 = 4-Me 68% (34+195)
1
218: R = 4-OMe 58% (36+195)
219: R1 = 4-Br 76% (40+195)
70% (85:15)c (32+206)
67% (81:19)c (32+208)
80% (81:19)c (32+210)
56% (90:10)c (32+212)
OH
N
195
52
N
N2
N
Ts
TsN
203 83c
H
N
195
50
N
Ts
N
N2
204 77c
H
OH
Me
10d
195
62
N
N2
Me N
H
H
205
OH
N
N
N2
32
32
32
32
32
R
206: R = i-Pr
208: R = CH=CH2
210: R = CH2CH=CH2
212: R = Ph
214: R = CH2OMOM
28d,e
(exo/endo = 85:15)f,g
OH
11
12
13
14
15
H
H
R
OH
9d
Mn(acac)3
(10 mol%)
NaBH3CN
(3 equiv)
HCl in MeOH
(3 equiv)
MeOH, r.t.
R2
(1.2 equiv)
N
N2
N
TsN
8
OH
+
OH
OH
1
2
3
4
5
6
7
R1
Yield/%b
Products
R
One-Pot Synthesis of 2-Azabicyclo[3.3.1]nonanesa,b
Table 11
H
R
H
207: 90 (exo/endo = 85:15)f
209: 82 (exo/endo = 83:17)f,g
211: 86 (exo/endo = 86:14)f,h
213: 91 (exo/endo = 94:6)f,g
215: 74 (exo/endo = 85:15)f
a
The reactions were carried out by the addition of a solution of the
cyclopropanol (1.2 equiv) in MeOH, via a syringe pump over 1 h, to
a solution of the vinyl azide (0.3 mmol) and Mn(acac)3 (10 mol%) under a N2 atmosphere at r.t.; this was followed by treatment with
NaBH3CN (3 equiv) and HCl in MeOH (3 M, 3 equiv) for 3 h.
b
Isolated yields are shown next to the corresponding products.
c
The ratio of the exo- and endo-isomers was determined by 1H NMR
spectroscopy, and the major exo-isomer is shown.
reduction of acetate 224 with triethylsilane induced selective carbon–oxygen bond cleavage, affording 2-azabicyclo[3.3.1]non-2-ene 225 in 90% yield, keeping the
carbon–nitrogen double bond intact. Similarly, treatment
with trimethylaluminum or allyltrimethylsilane–TiCl4
provided a new quaternary carbon center36 at the bridgehead position, giving products 226 and 227, respectively.
These transformations might proceed via a bridgehead
carbocation,37 which is then immediately trapped by the
corresponding nucleophile.
OH
a
Unless otherwise noted, the reactions were carried out by the addition of a solution of the cyclopropanol (1.2 equiv) in MeOH, via a syringe pump over 1 h, to a solution of the vinyl azide (0.3 mmol) and
Mn(acac)3 (10 mol%) under a N2 atmosphere at r.t.
b
Isolated yields unless otherwise noted.
c
5 mol% of Mn(acac)3 was used.
d
40 mol% of Mn(acac)3 was used.
e
Vinyl azide 62 was recovered in 68% yield.
f
The ratio was determined by 1H NMR spectroscopy, and the major
exo-isomer is shown.
g
The structures of exo-isomers 205, 209, and 213 were secured by Xray crystallographic analyses.
h
NMR spectroscopic yield, using Cl2CHCHCl2 as an internal standard, owing to the instability of 211; this product could be isolated as
its acetate in 73% yield on treatment of the crude mixture of 211 with
Ac2O (8.0 equiv), Et3N (2.0 equiv), and DMAP (0.1 equiv) in CH2Cl2
at r.t. for 8 h.
N
H
a. Ac2O
86%
H
b. TiCl4
Et3SiH
90%
N
H
OAc
196
225
N
H
224
Me
N
H
N
d. TiCl4
c. Me3Al
83%
H
TMS
227
82%
226
A proposed mechanism
O
Lewis acids
(LA)
224
LA
Me
AcO
O
LA
N
Ph
H
Nu–
Nu
N
Ph
H
N
Ph
H
225–227
Scheme 14
196. This one-pot/two-step process represents a straightforward procedure for the construction of the morphan
framework from readily available vinyl azides and bicyclic cyclopropanols (Table 11).26a
Further methods for the reduction of the carbon–oxygen
bond at the bridgehead position were explored using acetate 224 prepared from alcohol 196 (Scheme 14).26 Interestingly, the titanium(IV) chloride (TiCl4) mediated
© Thieme Stuttgart · New York
Melinonine-E (228) has been isolated from the bark of
Strychnos melinoniana,38 and its structure is characterized
by a unique pentacyclic ring system including indolo[2,3a]quinolizidine and morphan frameworks.39 The first synthesis of (±)-melinonine-E (228) was accomplished by
Bonjoch and co-workers.40 We envisaged that the 2-azabicyclo[3.3.1]nonane moiety of melinonine-E (228) could
be constructed by the Mn(III)-mediated [3+3]-annulation
Synlett 2012, 23, 21–44
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Entry
31
Applications of Organic Azides for the Synthesis of Nitrogen-Containing Molecules
ACCOUNT
S. Chiba
of vinyl azide 50 and a bicyclic cyclopropanol bearing a
hydroxymethyl-type tether, followed by the reduction of
the carbon–nitrogen double bond and bridgehead carbon–
oxygen bond in intermediate II to give I (Scheme 15).
The construction of the C-ring of melinonine-E (228) was
planned at a later stage.
OH
OH
+
TsN
C
A
B
N
C-ring
construction
E
D
A
OH
N
H H
H
melinonine-E 228
N3
OTBDPS
50
N
Ts
H
N
D
H
H
OTBDPS
N
Ts
H
OH
E
N
H
Mn(III)
OR
+
TsN
231
MeO
e. MeO CHO
NaB(OAc)3H
H
H
N
MeO
MeO
H
H
N
OR
N
H
H
OR
232 (R = TBDPS or H)
[3+3]-annulation
233: R = TBDPS; 43% (from 231)
N3
II
f. TBAF
93%
OR
50
Scheme 15
HO
g. BBr3
[3+3]-Annulation of 1-indol-2-ylvinyl azide (50) and bicyclic cyclopropanol 229 afforded azabicyclic compound
230 in 88% yield on a 2-gram scale in a diastereoselective
manner (exo/endo = 85:15), although 1.6 equivalents of
Mn(acac)3 were needed to complete the reaction
(Scheme 16).26a After the conversion of alcohol 230 into
its acetate, the bridgehead carbon–oxygen bond was reduced using the Et3SiH–TiCl4 protocol to afford cyclic
imine 231. Subsequent reduction of the carbon–nitrogen
double bond of 231 with lithium aluminum hydride–aluminum trichloride41 led to not only the entire reduction of
the imine and N-tosyl moieties, but also partial removal of
the tert-butyldiphenylsilyl (TBDPS) group. Reductive Nalkylation of the resulting secondary amines of 232 with
dimethoxyacetaldehyde in the presence of sodium triacetoxyborohydride provided 233 and 234 in 43 and 12%
yield, respectively. The remaining TBDPS group in 233
was removed with tetrabutylammonium fluoride. Boron
tribromide induced cyclization of 234 proceeded cleanly
to afford cyclic alcohol 235, which underwent dehydration with maleic acid in water followed by dehydrogenation with palladium black in a one-pot manner42 to afford
(±)-melinonine-E (228) as a perchlorate salt in 44% yield
from 234. The 1H and 13C NMR spectroscopic data of the
synthetic (±)-melinonine-E perchlorate were identical to
those previously reported.39,40a
2.4
H
OR
H
H
D
d. LAH, AlCl3
N
c. TiCl4, TES
(83%)
E
H
230
(exo:endo = 85:15)
229
I
N
B
B
N
Ts
OH
A
H
OTBDPS
N
Ts
88%
b. Ac2O (87%)
H
N
a. Mn(acac)3
Synthesis of Isoquinolines from a-Aryl-Substituted Vinyl Azides and Internal Alkynes
by Rhodium–Copper Bimetallic Cooperation
As mentioned in Section 2.1, vinyl azides readily undergo
thermal denitrogenation to afford highly strained threemembered cyclic imines, 2H-azirines, which can be regarded as vinylnitrene equivalents (Scheme 17). We
turned our attention to the use of these nitrogen atoms derived from a-aryl-substituted vinyl azides to direct a metal
complex for ortho C–H metalation,43 which might be followed by a carbon–carbon and carbon–nitrogen bond for-
234: R = H; 12% (from 231)
H
H N
N
H
OH
H
H
235
ClO4–
h. maleic acid, H2O
then Pd black
H
N
then aq NaClO4
44% (from 234)
N
H H
H
melinonine-E 228
OH
Scheme 16 Synthesis of (±)-melinonine-E (228); reagents and conditions: (a) 229 (3.0 equiv, added by a syringe pump), Mn(acac)3 (1.6
equiv), MeOH, r.t., 8 h, 88% yield; (b) Ac2O (8.0 equiv), Et3N (2.0
equiv), DMAP (0.1 equiv), CH2Cl2, r.t., 12 h, 87% yield; (c) TiCl4
(1.5 equiv), Et3SiH (2.0 equiv), CH2Cl2, r.t., 4 h, 83% yield; (d) AlCl3
(5.0 equiv), LAH (15.0 equiv), r.t., 30 h; (e) (MeO)2CHCHO (1.5
equiv), NaB(OAc)3H (1.5 equiv), CH2Cl2, 0 °C, 30 min, 43% yield of
233 + 12% yield of 234 (both from 231); (f) TBAF (1.5 equiv), THF,
r.t., 36 h, 93% yield; (g) BBr3 (8.0 equiv), CH2Cl2, –78 °C, 3 h; (h)
maleic acid (6.0 equiv), H2O, r.t., overnight, then Pd black (excess),
reflux, 50 h; aq NaClO4 (3.0 equiv), r.t., 44% yield (from 234)
mation sequence with internal alkynes to construct
azaheterocyclic frameworks.
It has been revealed that the combined use of [Cp*RhCl2]2
(Cp* = pentamethylcyclopentadienyl) and metal acetates
generates Cp*Rh(OAc)n species and results in deprotonative carbon–hydrogen bond cleavage with the aid of an intramolecular directing group, such as an imino group, to
afford rhodacycles.44,45 The application of this strategy for
the synthesis of various kinds of heterocycles has been
studied using reactions with internal alkynes.46,47 Based
on these background reports, we embarked on our investigation of the reaction of 1-phenylvinyl azide (32) and
diphenylacetylene (236) using [Cp*RhCl2]2 as a catalyst
N2
N
R
R'
vinyl azides
Δ
– N2
N
R
R'
vinylnitrenes
N
R
R'
2H-azirines
–Can these nitrogens (N) direct a metal complex
to the proximal C–H bond for ortho metallation?–
Scheme 17
Synlett 2012, 23, 21–44
© Thieme Stuttgart · New York
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32
Applications of Organic Azides for the Synthesis of Nitrogen-Containing Molecules
with carboxylate sources (Table 12) to target isoquinoline
derivatives.48 While the use of sodium acetate (NaOAc) or
cesium pivalate (CsOPiv) (30 mol%) as a carboxylate
source did not afford any ortho carbon–hydrogen bond
functionalization product (entries 1 and 2, respectively),
the reaction with copper(II) acetate [Cu(OAc)2] (20
mol%) at 110 °C in N,N-dimethylformamide (DMF) gave
1-methyl-3,4-diphenylisoquinoline (237) in 70% yield
(entry 3). The addition of 1 equivalent of AcOH allowed
for a lower reaction temperature (90 °C) and catalytic
loading of [Cp*RhCl2]2 (2.5 mol%) (entries 5 and 6). Notably, an acceleration of the reaction rate was observed using copper(I) acetate (CuOAc) instead of Cu(OAc)2 (entry
7).
Table 12 Optimization of the Reaction Conditions for the Synthesis
of Isoquinoline 237a
N2
N
cat. [Cp*RhCl2]2
additive-1
additive-2
+
Ph
Ph
Ph
Ph
236
DMF, conditions
32 (1.2 equiv)
N
Me
237
Entry
[Cp*RhCl2]2
/mol%
1
5
2
5
3
5
Cu(OAc)2 (20)
Additive-1
/mol%
Additive-2
/mol%
Conditions
Yield/%b
NaOAc (30)
110 °C, 12 h
0
CsOPiv (30)
110 °C, 12 h
0
110 °C, 0.3 h
70
4
5
Cu(OAc)2 (20)
H2O (100)
90 °C, 1 h
67c
5
5
Cu(OAc)2 (20)
AcOH (100)
90 °C, 0.6 h
80
6
2.5
2.5
Cu(OAc)2 (20)
CuOAc (20)
AcOH (100)
AcOH (100)
90 °C, 2 h
90 °C, 0.5 h
84
84
7
a
All reactions were carried out using 0.5 mmol of alkyne 236 with 1.2
equiv of vinyl azide 32 under a N2 atmosphere.
b
Isolated yields, unless otherwise noted, based on alkyne 236.
c
NMR spectroscopic yield.
Using the [Cp*RhCl2]2 (5 mol%)–Cu(OAc)2 (20 mol%)
catalytic system, the generality of this method was examined for the synthesis of substituted isoquinolines and other derivatives (Table 13).48 Wide substrate tolerance was
observed with the use of internal alkynes (entries 1–8).
The reactions with diarylacetylenes proceeded smoothly
with vinyl azide 32, giving isoquinolines in good yields
(entries 1–3). Dialkylacetylenes also resulted in reasonably smooth reactions (entries 4 and 5). The insertion of
unsymmetrical 1-phenylprop-1-yne (248) occurred in a
regioselective manner, affording 1,4-dimethyl-3-phenylisoquinoline (249) as the sole product (entry 6). Similarly,
methyl 3-phenylpropanoate (250) and 1-(2-thienyl)oct-1yne (252) provided isoquinolines 251 and 253 regioselectively, albeit in lower yields (entries 7 and 8, respectively). The introduction of electron-withdrawing groups as
substituents on the benzene ring of the a-aryl-substituted
vinyl azide resulted in isoquinoline formation in good
yields, whereas sluggish reactions were observed from vinyl azide 36, bearing the electron-donating methoxy moiety (entry 10), as well as from 1-(1-naphthyl)vinyl azide
(48) (entry 14). Carbon–bromine bonds could be kept intact in the synthetic process (entries 3, 12, and 15). Regio© Thieme Stuttgart · New York
33
isomeric mixtures were obtained in the reactions of metasubstituted substrates, where the less sterically hindered
carbon–hydrogen bond was cleaved in a preferential manner (marked in blue) (entries 15 and 16). The construction
of b-carboline, 1H-pyrrolo[2,3-c]pyridine, benzofuro[2,3-c]pyridine, and benzothiopheno[3,2-c]pyridine
structures could be achieved using the above process (entries 17–20, respectively). The introduction of methyl, siloxymethyl, alkoxymethyl, and aminomethyl groups at the
b-position of the vinyl azide did not retard the process and
led to the corresponding isoquinolines in moderate to
good yields (entries 21–26).
To probe how both the rhodium and copper catalysts work
in the reaction mechanism, several control experiments
were conducted using vinyl azide 32 and alkyne 236
(Scheme 18).48
The incorporation of deuterium into the methyl group of
the isoquinoline product to give 279 was observed in the
reaction conducted in the presence of water-d2 (D2O) (5
equiv) (Scheme 18, part a), whereas this was not observed
in the reaction using DMF-d7 as a solvent.49 These results
suggest that the hydrogen atom at the resulting methyl
moiety is introduced not via a radical pathway, but in an
ionic manner.
Next, 2H-azirine 280, prepared by the thermal decomposition of vinyl azide 32, was subjected to the reaction with
alkyne 236 in the presence of [Cp*RhCl2]2 and metal acetates. The reaction with Cu(OAc)2 or CuOAc afforded
isoquinoline 237; no isoquinoline formation was seen
with NaOAc at all (Scheme 18, part b). Moreover, the reaction with CuOAc was completed within 10 minutes,
whereas that of Cu(OAc)2 needed 2 hours. The reaction of
vinyl azide 32 with 2 equivalents of CuOAc in the presence of AcOH gave acetophenone (282) in 48% yield,
presumably via hydrolysis of the putative N-unsubstituted
(N-H) imine 281 (Scheme 18, part c). Interestingly, the reaction with [Cp*RhCl2]2–Cu(OAc)2 under an oxygen atmosphere did not afford isoquinoline 237. In sharp
contrast, a carbon monoxide atmosphere promoted the
isoquinoline formation to give the product in 82% yield
within 0.5 hours (Scheme 18, part d).
These experimental results indicated that both rhodium
(Rh) and copper (Cu) are indispensable for inducing the
ortho carbon–hydrogen bond functionalization of 2Hazirine 280 in the reaction to give product 237. The lower
valent Cu(I) species might take part in the reductive ring
opening of the 2H-azirine to give the imine derivative,50
which then might be relayed to initiate Rh(III)-catalyzed
ortho C–H rhodation, followed by insertion of the alkyne.
In fact, the ultraviolet/visible (UV/vis) spectra for the
treatment of Cu(OAc)2 in DMF at 90 °C showed quenching of the visible band of Cu(OAc)2 at 700 nm. This observation suggests that a solvent amount of DMF might
reduce Cu(OAc)2 to form the Cu(I) species.51 The UV/vis
spectra for the treatment of [Cp*RhCl2]2 in DMF at 90 °C
showed no change of the visible band of [Cp*RhCl2]2 at
410 nm.
Synlett 2012, 23, 21–44
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ACCOUNT
ACCOUNT
S. Chiba
Table 13 Synthesis of Substituted Isoquinolines and Other Derivatives from a-Aryl-Substituted Vinyl Azides and Internal Alkynes Catalyzed by [Cp*RhCl2]2–Copper(II) Acetatea
Entry
Vinyl azides
+ Ph
R1
238 (R1, R2 = 4-MeOC6H4)
240 (R1, R2 = 4ClC6H4)
242 (R1, R2 = 4-BrC6H4)
244 (R1, R2 = n-Pr)
246 (R1 = CH2OTBS, R2 = CH2OTBS)
248 (R1 = Me, R2 = Ph)
250 (R1 = CO2Me, R2 = Ph)
252 (R1 = n-hexyl, R2 = 2-thienyl)
32
32
32
32
32
32
32
32
R
34 (R = Me)
36 (R = OMe)
44 (R = CO2Me)
40 (R = Br)
Ph
Ph
toluene
100 °C, 1.5 h
82%
(NMR yield)
N2
Ph
258
Me
N2
14
N
Me
R
42 (R = Br)
82 (R = NO2)
Ph
Ph
Ph
N2
N
236
N
Ts
52
19f
N
N
Ts
267
O
Me
S
24
25
N
Ph 269: 75%
S
R1
N2
N
R2
Ph
R1
R2
N
236 (R1, R2 = Ph)
244 (R1, R2 = n-Pr)
248 (R1 = Me, R2 = Ph)
62
62
62
Me
268: 45%
Me
236
54
N2
N
Ph
N
236
N N
2
21e
22e
23e
266: 77%
Me
Ph
N2
O
20
265: 82%
Me
Ph
18
Me
262: 12%
264: 5%
N
Ts
50
270: 85%
271: 54%
272:
80%
Me
Ph
Ph
273 (R = TBDPS)
275 (R = CH2CH=CH2)
OR
O
277
N
O
236
N
O
274: 46%
276: 40%
OR
Ph
Ph
26
N
236
236
N2
N
278: 85%
N
O
a
The reactions were carried out by treating a mixture of the vinyl
azide (1.2 equiv) and alkyne (0.5 mmol) with [Cp*RhCl2]2 (5 mol%)
and Cu(OAc)2 (20 mol%) in the presence of AcOH (1 equiv) in DMF
(2.5 mL) at 90 °C under a N2 atmosphere for 1–2 h.
b
Isolated yields unless otherwise noted.
c
1.5 equiv of vinyl azide 32 were used.
d
NMR spectroscopic yield.
e
2.5 mol% of [Cp*RhCl2]2 was used.
f
10 mol% of [Cp*RhCl2]2 was used.
Synlett 2012, 23, 21–44
Me
(c)
282 48%
Ph
Ph
236
N
Me
DMF, 90 °C
atmosphere
(d)
237
0%
82%
N
R
N
236
N
Ts
O
under O2
under CO (0.5 h)
N2
N
46%
52%
0%
Ph
N
R
261: 74%
263: 66%
Ph
236
236
237
2h
10 min
2h
(b)
Scheme 18
Ph
Ph
Me
N
+
260: 38%
Ph
N2
N
17
32
Ph
236
48
time
NH
[Cp*RhCl2]2 (2.5 mol%)
Cu(OAc)2 (20 mol%)
AcOH (1 equiv)
Me
N
Me
281
32
259: 70%
Me
N
Me
N
236
Ph
Ph
DMF, 90 °C
Ph
13
15
16
CuOAc (2 equiv)
AcOH (2 equiv)
N
254: 80%
255: 45%d
256: 86%
257: 80%
N2
N
280 (1.2 equiv)
DMF, 90 °C
time
M(OAc)n
Cu(OAc)2
CuOAc
NaOAc
R
236
236
236
236
236 (1.0 equiv)
[Cp*RhCl2]2 (5 mol%)
M(OAc)n (20 mol%)
AcOH (1 equiv)
32
Me
9
10
11e
12
279 60%
N
239: 77%
241: 70%
243: 83%
245: 71%
247: 54%
249: 82%
251: 27%
253: 52%d
Ph
Ph
N
N2
N
CDnH3–n (a)
(n = 1.62)
32
Me
2
N
DMF, 90 °C, 3.5 h
236
N
R2
Ph
Ph
R2
R1
Ph
[Cp*RhCl2]2 (2.5 mol%)
Cu(OAc)2 (20 mol%)
D2O (5 equiv)
N
Isoquinolines / yieldb
Alkynes
N2
N
1
2
3c
4
5
6
7
8
N2
Based on these experimental data, a possible mechanism
under the [Cp*RhCl2]2–Cu(OAc)2 catalytic system was
proposed, as outlined in Scheme 19. First, the Cu(I) species is formed via the reduction of Cu(OAc)2 by DMF
(step i). 2H-Azirine 280, generated by thermal denitrogenative decomposition of vinyl azide 32, is reduced by the
Cu(I) species to afford radical anion A (step ii, path a).
Ring opening by carbon–nitrogen bond cleavage of A
forms iminylcopper(II) radical intermediate B, which is
further reduced with Cu(I) and protonated to give N-H
imine 281 along with the Cu(II) species. Alternatively, it
can be proposed that the direct reduction of vinyl azide 32
by the Cu(I) species forms the putative radical intermediate B via vinyl azide radical anion E (step ii, path b). The
formation of rhodacycle G from N-H imine 281 or iminylcopper intermediate D with Rh(III) via iminyl rhodium F,
followed by insertion of alkyne 236 and subsequent carbon–nitrogen bond formation through reductive elimination from H, provides isoquinoline 237 with the
generation of the Rh(I) species (step iii). Finally, a redox
reaction between the Rh(I) and Cu(II) species leads to the
regeneration of Rh(III) and Cu(I) (step iv).
The reductive formation of imine derivatives from vinyl
azides is supposed to proceed via the protonation of copper(II) azaenolates, such as C (Scheme 19, step ii). We
aimed to trap such putative azaenolates with other electrophiles for the further functionalization of isoquinoline derivatives. After the extensive screening of various
electrophiles, it was found that the addition of TEMPO
(2,2,6,6-tetramethylpiperidin-1-yloxyl) (2 equiv) instead
of AcOH in the reaction of vinyl azides 62 and 277 with
several alkynes under the [Cp*RhCl2]2–Cu(OAc)2 catalytic system delivered isoquinoline–TEMPO adducts and
© Thieme Stuttgart · New York
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34
(i) generation the of Cu(I) species by reduction of Cu(OAc)2 with DMF
O
Me
[CuI]
CuII(OAc)2 +
H
N
Me (DMF)
(ii) reductive formation of NH imines from vinyl azides and the Cu(I) species
N2
N
Ph
[CuI]
N
280
Ph
A
[Cu ]
H
[CuII]
[CuII]
[CuII]
[CuI]
N
N
– N2
Ph
E
N2
[Cp*RhCl2]2 (2.5 mol%)
Cu(OAc)2 (20 mol%)
N
R2
B
path b
[CuII]
Ph
Me
281
+
R3
Ph
Entry
H
281 or D
[Rh ] N
N
1
236
N
Ph
n-Pr
H
G
F
– [RhI]
62
3
Me
2 [CuII]
+
[RhIII] +
2 [CuI]
N
4c
alcohols in good combined yields (Table 14).48,52 From vinyl azide 277, a b-amino alcohol unit could be installed in
the isoquinoline framework (entry 4). Although we are
not certain as to the reaction mechanism of this carbon–
oxygen bond formation, one possibility might be the nucleophilic attack of the azaenolate carbon to a Cu(II)–
TEMPO complex, which would act as an ionic electrophile.
3
Chemistry of Cyclic 2-Azido Alcohols
3.1
Manganese(III)-Catalyzed Ring Expansion
of 2-Azidocyclobutanols
Following the above-mentioned formal [3+2]- and [3+3]annulation strategies of vinyl azides via an iminylmanganese(III) species as a key intermediate, we planned an alternative method for generating such metal species using
the metal-mediated b-fission (b-carbon elimination) of
cyclic 2-azido alcohols.53 As shown in Scheme 20 as an
example, the oxidative b-fission of 2-azidocyclobutanol
or -cyclopentanol would provide iminyl radical/metal
species along with the formation of an intramolecular carbonyl moiety, which would cyclize to afford the corresponding heterocycles, such as pyrrole (n = 1) or pyridine
(n = 2), respectively.
n
N N N
Ph
O
277
– [Mn–1]
n
N N N
n
N N N
O
– N2
n
N
Scheme 20
© Thieme Stuttgart · New York
Ph
283: 68%
284: 15%
n-Pr
285: 39%
286: 42%
Ph
287: 55%
288: 18%
289: 48%
290: 29%
Ph
236
a
All reactions were carried out using 0.5 mmol of the alkyne with 1.5
equiv of the vinyl azide under a N2 atmosphere.
b
Isolated yields are shown based on the alkyne.
As expected, the catalytic conversion of 2-azidocyclobutanols proceeded smoothly with Mn(pic)3 to give the corresponding pyrroles 291–293 in excellent yields,54
whereas that of 2-azidocyclopentanol or -cyclopentenol
derivatives was unsuccessful (Scheme 21).55 This suggested that the release of the ring strain is indispensable as
a key driving force of this Mn(III)-catalyzed b-fission
strategy.
R
N
Mn
O
HO
N
N2
O
3
(10 mol%)
MeOH, 0 °C, 0.5 h
then 40 °C, 3 h
N
H
R
291 (R = H); 90%
292 (R = Me); 88%
293 (R = Cl); 89%
OH
Mn(III)
N N2
N
no reaction
0%
Scheme 21
3.2
Palladium(II)-Catalyzed Ring Expansion of
Cyclic 2-Azido Alcohols
O
O
[Mn]
Alcoholsb
O
[Rh] = Cp*Rh(OAc)n
Scheme 19
OH
TEMPO
adductsb
248
N2
N
(iv) redox regeneration of the Rh(III) and Cu(I) species
[RhI]
OH
R1
alcohols
244
Me
237
N
+
236
2
Me
– H+
– H+ or
– Cu(II)
Ph
N2
N
Ph [RhIII]
Ph
Me
Me
N
O
Alkynes
Vinyl azides
(iii) ortho C–H rhodation, alkyne insertion, and C–N reductive elimination
[RhIII]
N
Me
D
III
R3
R2
R1
TEMPO adducts
N
– [CuII]
Ph
DMF, 90 °C, 1 h
[CuII]
C
[RhIII]
N
O
(2 equiv)
R2
[CuII]
+
H+
N
Ph
R3
R1
(1.5 equiv)
NH
Ph
Ph
– N2
[CuII]
N
I
N2
Table 14 Reaction of Vinyl Azides and Internal Alkynes with
2,2,6,6-Tetramethylpiperidin-1-yloxyla
+
path a
32
35
Applications of Organic Azides for the Synthesis of Nitrogen-Containing Molecules
N
H
(n = 1)
or
N
(n = 2)
Further extensive investigations revealed that a palladium(II) [Pd(II)] catalyst system could achieve the ring-expansion reaction of nonstrained cyclic 2-azidopentenol
derivatives.56 The reaction involves an unprecedented carbon–carbon bond cleavage57 and carbon–nitrogen bond
formation sequence to provide azaheterocycles, such as
pyridine and isoquinoline derivatives.
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S. Chiba
As a model substrate, (1R*,5R*)-5-azido-2,3-diphenylcyclopent-2-enol (trans-294) was selected, and its reactions
under Pd catalyst systems (with 1 equiv of K2CO3 in
DCE) were examined.56 While Pd(II) complexes themselves did not exhibit any reactivity, they showed interesting catalytic effects in the presence of phosphine and
nitrogen ligands, giving the ring-expansion product 3,4diphenylpyridine (295) (Scheme 22). Extensive ligand
screening revealed that bidentate ligands worked efficiently with Pd(II) catalysts for the pyridine formation,
and the use of PdCl2(dppf) [dppf = 1,1¢-bis(diphenylphosphino)ferrocene] (15 mol%) at 80 °C gave 295 in the best
yield (88%). Interestingly, Pd(OAc)2 with bidentate nitrogen ligand 2,2¢-bipyridine also exhibited good catalytic
activity. The reactions of the corresponding cyclic cis-2azido alcohol cis-294 also proceeded to form pyridine
295, although the yield of 295 was lower than that from
trans-294. It was also noted that other metal complexes,
such as nickel(II), Cu(I), Rh(I), and gold(I) complexes,
were not viable catalysts for this transformation.
OH
Ph
N3
Ph
trans-294
Pd catalyst, ligand
K2CO3 (1 equiv)
Ph
DCE
80 °C
Ph
N
295
PdCl2(dppf) (15 mol%), 5 h 88%
Pd(OAc)2–2,2'-bipyridine (15 mol%), 0.5 h 80%
OH
Ph
PdCl2(dppf) (15 mol%)
K2CO3 (1 equiv)
Ph
DCE
80 °C, 4 h
Ph
N3
Ph
cis-294
N
295 59%
Scheme 22 Optimized reaction conditions for the palladium-catalyzed ring expansion of cyclic 2-azido alcohols
As shown in Scheme 23, the catalytic cycle could be initiated by b-carbon elimination of palladium(II) alcoholate
I, generated from azido alcohol 294 with a Pd(II) complex
in the presence of a base. It was speculated that this process might be promoted by the coordination of the internal
nitrogen of the azido moiety to the metal center.58 The
subsequent elimination of molecular nitrogen provides
iminylpalladium(II) species II, which undergoes intramolecular nucleophilic attack to the resulting carbonyl group,
affording cyclized intermediate III. Protonation of III followed by dehydration affords pyridine 295 along with the
Pd(II) complex. Alternatively, elimination of a hydroxidopalladium(II) species from III provides 295 directly.
The generality of this catalytic ring expansion for the synthesis of substituted pyridines was next examined using
trans-azido alcohols (Table 15).56 The method allowed
the installation of not only aryl substituents, but also methyl and allyl groups at C-3 of the pyridine ring. 3,4-Dialkyl-substituted pyridine 302 could also be synthesized
in good yield. Importantly, 3-chloro- and 3-bromopyridines 303 and 304 could be prepared with the carbon–
Synlett 2012, 23, 21–44
OH
Ph
Ph
Ph
N
H2O
295
Ph
[PdII]
Ph
N N N
[PdII]
Ph
IV
H+
O
Ph
[PdII]–OH
OH
Ph
N
H+
294
O [PdII]
Ph
N
N N N
Ph
III
O
I
[PdII]
Ph
N
Ph
N2
II
Scheme 23
chlorine and carbon–bromine bonds, respectively, intact.
3-Arylpyridines with some substituents were available using this method.
This catalytic ring expansion could be applied to the synthesis of substituted isoquinoline derivatives from the corresponding azidoindanols (Table 16).56 It should be noted
that the reactions of both trans-1-azidoindan-2-ol and
trans-2-azidoindan-1-ol derivatives afforded the same
isoquinolines. Interestingly, the reactions of the 2-azidoindan-1-ol derivatives, such as 312 and 315, proceeded at
room temperature using a Pd(OAc)2–dppf system to give
the products in excellent yields. Both electron-withdrawing and electron-donating groups were incorporated on
the isoquinoline ring. Chloro substituents on the benzene
ring were tolerated. Azido alcohols bearing a phenyl
group at C-3 or C-2, such as in 322 and tertiary alcohol
324, respectively, were converted into the corresponding
isoquinolines in good yields. Moreover, this method also
afforded g-carboline 327 from substrate 326.
Table 15
Synthesis of Pyridines from Cyclic 2-Azido Alcoholsa,b
PdCl2(dppf) (15 mol%)
K2CO3 (1 equiv)
OH
R1
N3
DCE
80 °C
R2
R
R1
Me
Me
N
Me
N
N
R2
N
N
Me
296; R = Me: 78%
297; R = Cl: 88%
298; R = F: 89%
Me
302: 65%
299: 83%
X
N
300: 74%
N
303; X = Cl: 90%
304; X = Br: 72%c
R
301: 80%
305; R = H: 83%d
306; R = Me: 64%
N 307; R = Cl: 84%
308; R = F: 86%
309; R = CF3: 93%
a
Unless otherwise noted, the reactions were carried out using 0.3
mmol of the azido alcohol in the presence of 15 mol% of PdCl2(dppf)
and 1 equiv of K2CO3 in DCE (2 mL) at 80 °C under a N2 atmosphere.
b
Isolated yields are shown next to the corresponding products.
c
The reaction was run using 10 mol% of Pd(OAc)2 and 2,2¢-bipyridine as a catalyst.
d
20 mol% of PdCl2(dppf) was used.
© Thieme Stuttgart · New York
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36
Synthesis of Isoquinolines and g-Carbolinea,b
Table 16
Products (yield/%)b trans-Azidoalcohols Products (yield/%)b
trans-Azidoalcohols
X
EtO2C
MeO2C
N
N3
Cl
Y
X
O
O
Y
OH
N3
Ph
Ph
325 (62)d
OH
N
N
Ts
Me 319 (90)
318
Me
Ph
324
N
N3
N
OH
Me
OH
Ph
323 (73)
N3
N
317 (96)c
Ph
N
Ph 322
Cl
316
321 (90)
Cl
OH
MeO
MeO
N
N3
N
313 (X = N3, Y = OH) 314 (76)
315 (X = OH, Y = N3) 314 (92)c
Me
320
Cl
O
O
Cl
OH
310 (X = N3, Y = OH) 311 (81)
312 (X = OH, Y = N3) 311 (96)c
Cl
N3
326
N
Ts
Unless otherwise noted, the reactions were carried out using 0.3
mmol of the azido alcohol in the presence of 15 mol% of PdCl2(dppf)
and 1 equiv of K2CO3 in DCE (2 mL) at 80 °C under a N2 atmosphere.
b
Isolated yields are shown next to the corresponding products.
c
The reaction was carried out using 10 mol% of Pd(OAc)2 and 10
mol% of dppf at r.t.
d
20 mol% of PdCl2(dppf) was used.
Chemistry of a-Azido Carbonyl Compounds
4.1
1).62 The reaction could also be used to install methyl and
benzyl groups, as well as some cycloalkyl moieties and an
alkene tether, at the C-3 position of the isoindole (entries
2–8). The reaction of azide 344 bearing a 4-toluoyl group
instead of ethoxycarbonyl also proceeded smoothly to
give 1-toluoylisoindole 345 in 85% yield (entry 9). A fluorine or bromine atom could be introduced at the C-5 or
C-4 position of the isoindole ring (entries 10 and 11, respectively). It is noteworthy that 6H-pyrrolo[3,4-b]pyridine 351 was readily accessible using this method (entry
12).
Following this discovery of the formation of isoindoles
via azide–alkene 1,3-dipolar cycloaddition, it was found
that the treatment of azide 328 with potassium carbonate
(K2CO3) (5 equiv as a base) and EtOH (10 equiv as a proton source) in 1,3-dimethylimidazolidin-2-one (DMI) (0.3
327 (93)
a
4
Table 17 Synthesis of Isoindole Derivatives from a-Azido Carbonyl Compoundsa
Entry
Azides
R1
Isoindoles and their derivatives are attractive candidates
for organic light-emitting devices (OLEDs) owing to their
good fluorescent and electroluminescent properties.59
They show high reactivity in [4+2] cycloadditions with
various dienophiles for the preparation of oligoacenes.60
We envisaged that the intramolecular azide–alkene cycloaddition reaction61 of readily available a-azido carbonyl compound 328, bearing a 2-alkenylaryl moiety at the aposition, and the subsequent elimination of molecular nitrogen from the resulting triazoline would produce isoindole 329, as shown in Scheme 24.
The expected isoindole formation proceeded smoothly on
heating azide 328 in toluene (0.1 M concentration) at 100
°C, giving isoindole 329 in 98% yield (Table 17, entry
Me Me
N
N N
Me
N
N
CO2Et
328
N
Δ
azide–alkene
cycloaddition
Me Me
H
N2
N
CO2Et
triazoline
Me
Me
Me
N
Me
NH
– N2
CO2Et
Scheme 24
© Thieme Stuttgart · New York
CO2Et
isoindole 329
R1
328 (R1, R2 = Me)
330 (R1, R2 = H)
332 (R1 = Ph, R2 = H)c
N3
5
6
7
R2
NH
1
334 R2 = 4-MeOC6H4
CO2Et
R =H
( )n
4
CO2Et
N3
8
NH
Me
Me
Me
344
NH
345 85%
COp-Tol
COp-Tol
Me
343 82%
CO2Et
CO2Et
N3
335 (87%)
CO2Et
342
9
329 98% (83%)
331 94% (75%)
333 (99%)
337 (87%)
339 (70%)
341 (54%)
NH
N3
Me
Yieldb
( )n
336 (n = 4)
338 (n = 2)
340 (n = 1)
CO2Et
Me
Me
Me
F
F
10
346
NH
N3
Br
Me
348
11
347 (82%)
CO2Et
CO2Et
Br
NH
349 (57%)
N3
Me
CO2Et
CO2Et
Me
12
Me
350
N
CO2Et
Isoindoles
R2
1
2
3
Orthogonal Synthesis of Isoindole and Isoquinoline Derivatives
Me
37
Applications of Organic Azides for the Synthesis of Nitrogen-Containing Molecules
N3
CO2Et
Me
NH
351 (61%)
N
CO2Et
a
The reactions were carried out by heating the azide in toluene (0.1
M) at 100 °C for 3 h.
b
In parentheses is the two-step yield from the corresponding mesylate. In this case, the product was obtained by treating the mesylate
with NaN3 (1.2 equiv) in DMF (0.3 M) at 0 °C, followed by workup
and then heating the resulting crude azide in toluene (0.1 M) at 100
°C for 3–5 h.
c
Z/E = 5.4:1.
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S. Chiba
M concentration) at 40 °C induces denitrogenation to provide N-H imine 352.63 Subsequent 6p-electrocyclization64
of the resulting azahexatriene moiety of 352 was observed
to be promoted by diluting the concentration with toluene
(0.1 M) and heating at 100 °C, giving dihydroisoquinoline
353 in 95% yield (Scheme 25, part a). Based on this finding, the direct transformation of mesylate 354 into dihydroisoquinoline 353 was also achieved in 90% yield on
treatment of 354 with sodium azide (1.2 equiv), K2CO3 (5
equiv), and EtOH (10 equiv) in DMI at 40 °C, followed by
cyclization of the resulting imine 352 in toluene–DMI at
100 °C (Scheme 25, part b).62
sponding 4-methylisoquinoline 379 in 65% yield (entry
11).
4.2
Generation of Iminylcopper Species and
Their Catalytic Carbon–Carbon Bond
Cleavage under an Oxygen Atmosphere
Based on the above-mentioned isoquinoline formation via
N-H imine intermediates, we next explored the generation
Table 18 Synthesis of Isoquinoline and Dihydroisoquinoline Derivativesa
Mesylate
Entry
Me
Me
N2
N
CO2Et
328
Me
Me
K2CO3 (5 equiv)
EtOH (10 equiv)
DMI (0.3 M)
40 °C, 1 h
Me
Me
NH
CO2Et
352
add toluene
(0.1 M)
100 °C, 8 h
1b
OMs
Me
N
OMs
CO2Et
354
NaN3 (1.2 equiv)
K2CO3 (5 equiv)
EtOH (10 equiv)
DMI (0.3 M)
40 °C, 1 h
imine
352
Me
N
(0.1 M)
100 °C, 8 h
356 (82)
N
CO2Et
Ar
Ar
Ar
OMs
N
CO2Et
Me
add toluene
355
CO2Et
CO2Et
353 95% (a)
Me
Isoquinolines (yield/%)
357 (Ar = Ph)c
360 (Ar = 4-MeOC6H4)
2b
3b
N
CO2Et
CO2Et
358 (52)
361 (50)
359 (16)
362 (14)
CO2Et
353 90% (b)
4
OMs
Scheme 25
363
364 (96)
N
CO2Et
CO2Et
Me
This method resulted in the synthesis of a range of structurally diverse isoquinoline and dihydroisoquinoline derivatives from the corresponding mesylates (Table 18).62
From mesylate 355 bearing a vinyl group, the 6p-cyclization followed by oxidation of the resulting dihydroisoquinoline under an oxygen atmosphere gave ethyl
isoquinoline-1-carboxylate (356) in 82% yield (entry 1).
The reaction of styryl derivative 357 afforded 3-phenylisoquinoline 358 in 52% yield along with 4-phenylisoquinoline 359 (16% yield), which may have been formed
via rearrangement of the phenyl group during the aerobic
oxidation of the dihydroisoquinoline (entry 2). However,
mesylate 360 bearing a 4-methoxyphenyl group, which
has a higher migratory aptitude than a phenyl group, gave
a nearly identical distribution of products (entry 3). Dihydroisoquinoline 364 bearing a spirocyclohexane moiety
was successfully prepared in excellent yield from the
corresponding mesylate 363 (entry 4). Mesylate 365
possessing a cyclobutylidenemethyl moiety gave spirodihydroisoquinoline 366 in 71% yield along with 13%
yield of 3-propylisoquinoline 367, formed via ring opening of the cyclobutane moiety/aromatization (entry 5).
The cyclopropane moiety, however, could not be kept in
the corresponding reaction of 368 which resulted in only
3-ethylisoquinoline 369 in 88% yield (entry 6). Neither
the replacement of the ethoxycarbonyl moiety with a
4-toluoyl group nor the introduction of halogen atoms on
the aryl ring retarded the process (entries 7–9). In addition, 1,7-naphthyridine framework 377 could be constructed in good yield (entry 10). The reaction of mesylate
378 bearing a 1-methylvinyl group delivered the corre-
Synlett 2012, 23, 21–44
5
OMs
365
CO2Et
N
N
CO2Et
366 (71)
CO2Et
367 (13)
Me
368
6
OMs
N
CO2Et
Me
Me
OMs
7
CO2Et
Me
Me
370
F
8
COp-Tol
Me
F
372
Me
CO2Et
CO2Et
Br
OMs
375 (79)
374
N
CO2Et
10
N
373 (89)
N
Br
9b
371 (78)
N
COp-Tol
Me
Me
OMs
369 (88)
Me
Me
OMs
CO2Et
Me
N
N
Me
379 (65)
378
OMs
CO2Et
377 (77)
CO2Et
CO2Et
Me
11b
Me
376
N
CO2Et
a
Unless otherwise noted, the reactions were carried out by treating
the mesylate with NaN3 (1.2 equiv), K2CO3 (5 equiv), and EtOH (10
equiv) in DMI (0.3 M) at 40 °C for 1–3 h, followed by the addition of
toluene (0.1 M) and then heating at 100 °C for 8 h.
b
After the consumption of the imine, the mixture was purged with O2
and heated at 100 °C.
c
Z/E = 5.4:1.
© Thieme Stuttgart · New York
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38
ACCOUNT
39
Applications of Organic Azides for the Synthesis of Nitrogen-Containing Molecules
of iminylmetal species by trapping N-H imine 352 with
transition metals and we looked at their chemical reactivity. During the course of this study, it was found that the
treatment of N-H imine 352, generated from azide 328,
with 1 equivalent of Cu(OAc)2 at 60 °C under an argon atmosphere afforded unexpected benzonitrile 380 in 32%
yield instead of isoquinoline 353 (Scheme 26).65 It was
supposed that benzonitrile 380 was formed via oxidative
carbon–carbon bond cleavage between the imino carbon
and the ethoxycarbonyl carbon of the putative iminylcopper intermediate A.
resulting arenecarbonitriles, such as in products 382–388
and 389–394, respectively. Halogen atoms, such as bromine and fluorine, were also introduced into the products
with the reaction keeping the carbon–halogen bond intact,
as in the formation of 389–392. In addition, alkanecarbonitriles were synthesized using sodium ethoxide as a base.
In particular, the formation of tertiary carbonitriles 395
and 396 proceeded in good yields, whereas the reactions
to form secondary and primary carbonitriles 397 and 398,
respectively, were sluggish.
Table 19 Copper(II) Acetate Catalyzed Synthesis of Carbonitrilesa,b
Me
Me
K2CO3 (5 equiv)
EtOH (10 equiv)
N2
N
Me
NH
DMI, 40 °C, 1 h
under Ar
CO2Et
328
N2
N
Cu(OAc)2
(1 equiv)
R1
60 °C, 27 h
CO2Et
352
Me
Cu(OAc)2 (20 mol%)
K2CO3 (1 equiv)
Me
CN
CN
Me
R
382 (90)
CN
N [Cu]
C N
380 32%
384 (87)
(93%)
(90%)
(75%)
(72%)
389: R = 4-Br
390: R = 2-Br
391: R = 3,5-Br2
392: R = 3,5-F2
393: R = 4-CN
394: R = 4-CO2Me
(85%)
(47%)
(62%)c,d
(49%)c
(70%)c
(81%)c,e
Me Me
The optimization of this benzonitrile formation was investigated using ethyl 2-azido-2-(2-naphthyl)acetate (381)
(Scheme 27).65 Treatment of 381 with Cu(OAc)2 (1 equiv)
and K2CO3 (1 equiv) in DMF at 60 °C directly delivered
2-naphthonitrile (382) in 78% yield along with 3% yield
of a-keto ester 383, which is likely formed by the hydrolysis of the corresponding iminylcopper or N-H imine intermediate. In this case, the coordination of Cu(OAc)2 to
the internal nitrogen of the azido moiety might induce the
denitrogenative formation of the corresponding iminylcopper. A catalytic amount of Cu(OAc)2 under an argon
atmosphere could not complete the reaction. In sharp contrast, the reaction was dramatically accelerated under aerobic conditions. Under an oxygen atmosphere (1 atm),
nitrile 382 was obtained in 90% yield using 20 mol% of
Cu(OAc)2.
N2
N
CO2Et
Cu salts
K2CO3 (1 equiv)
DMF (0.1 M), 60 °C
atmosphere
Cu(OAc)2 (1 equiv) under Ar (24 h)
Cu(OAc)2 (20 mol%) under Ar (24 h)
Cu(OAc)2 (20 mol%) under O2 (7.5 h)
Scheme 27
385: R = 4-C6H5
386: R = 4-OMe
387: R = 2-OMe
388: R = 3,4-(OMe)2
alkanecarbon nitrilesf
Scheme 26
381
DMF (0.1 M), 60 °C
under O2 (1 atm)
arenecarbon nitriles
Me
CO2Et
A
R1 C N
CO2Et
O
CN
CO2Et
+
382
383
78%
11%
90%
3%
12%
3%
Optimized reaction conditions for the nitrile formation
With the optimized conditions in hand, the generality of
this catalytic method was examined for the synthesis of
carbonitriles using a-azido esters (Table 19).65 The process provided the decarboxylated, one-carbon-shorter carbonitriles from the corresponding carboxylic acid
derivatives. The reaction allowed the installation of both
electron-donating and electron-withdrawing groups in the
© Thieme Stuttgart · New York
CN
395 (91%)
CN
396 (64%)
CN
Ph
397 (28%)
CN
398 (37%)
a
The reactions were carried out using 0.3 to 0.55 mmol of the azide.
Isolated yields are shown in parentheses next to the corresponding
products.
c
The reactions were run by treating the corresponding bromide (for
391) or mesylate (for 392–394) with NaN3 followed by Cu(OAc)2 and
K2CO3 under O2 (1 atm).
d
40 mol% of Cu(OAc)2 was used at 80 °C.
e
A methyl ester was used as the starting material.
f
1 equiv of NaOEt was used as a base.
b
In the reaction of substrate 399 bearing a biphenyl-2-yl
group with 40 mol% of Cu(OAc)2, benzonitrile 400 was
formed in 55% yield along with 41% yield of phenanthridine 401, which was presumably synthesized by carbon–
nitrogen bond formation involving an aromatic carbon–
hydrogen bond and a putative iminylcopper species
(Scheme 28).65,66 The stoichiometric use of Cu(OAc)2 improved the yield of benzonitrile 400 to 74% (formed along
with 20% yield of 401).
N2
N
CO2Et
Cu(OAc)2
K2CO3 (1 equiv)
N
CN
+
CO2Et
DMF (0.1 M), 60 °C
under O2 (1 atm)
400
401
40 mol% of Cu(OAc)2
55%
41%
100 mol% of Cu(OAc)2
74%
20%
399
Scheme 28
To probe the reaction mechanism of this catalytic cycle
with a special interest in the identification of any co-products derived from the carbonyl fragment after carbon–
carbon bond cleavage and the role of the molecular oxySynlett 2012, 23, 21–44
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Me
ACCOUNT
S. Chiba
gen, substrates 402 and 404 were employed in the above
catalytic carbonitrile formation (Schemes 29 and 30, respectively).65
The reaction of 2,4,4-trimethyl-1-pentyl ester 402 afforded 2-naphthonitrile (382) and 2,4,4-trimethylpentan-1-ol
(403) in 81 and 72% yield, respectively (Scheme 29).
Interestingly, the treatment of a-keto azide 404 provided
benzonitrile 386 and the corresponding benzoic acid 405
(Scheme 30, part a). The use of isotope oxygen (18O2) revealed that one of the oxygen atoms from the molecular
oxygen is incorporated into the benzoic acid. The reaction
of 404 in the presence of styrene (406) (1 equiv) under the
catalytic conditions gave benzonitrile 386 (76% yield)
and benzoic acid 405 (54% yield) along with styrene oxide (407) in 9% yield (analyzed by GC) (Scheme 30, part
b). This indicated that an (acylperoxy)copper species67
might be involved in the catalytic cycle.
N3
Cu(OAc)2 (20 mol%)
K2CO3 (1 equiv)
O
O
DMF (0.1 M), 60 °C
under O2 (1 atm)
402
bonyl compound on elimination of molecular nitrogen via
the deprotonation of I. The oxidation of II with oxygen affords peroxycopper(III) species III, which adds to the intramolecular carbonyl group to induce carbon–carbon
bond cleavage delivering the carbonitrile and (acylperoxy)copper IV. Protonation of (acylperoxy)copper species IV provides carboxylic acid V with the regeneration
of the Cu(II) salt. When ester substrates are used, further
decarboxylation of V proceeds to afford the corresponding alcohols.
The stoichiometric reaction under an argon atmosphere
(see Scheme 27) indicated that iminylcopper(II) II could
form the carbonitrile and acylcopper VI by b-carbon elimination as another mechanistic possibility (Scheme 32,
path a). In addition, it could also be speculated that peroxycopper III undergoes b-fission to lead to the formation of
the carbonitrile and acylcopper VII, which isomerizes to
(acylperoxy)copper IV (path b).
CN
+ HO
path a
[CuII]
N
403 72%
382 81%
R1
Scheme 29
[CuII]
R2
O
O
[CuIII]
O2
O
VI
R1–CN
O
II
R2
R2
O
VII
[CuII]
Cu(OAc)2 (20 mol%)
K2CO3 (1 equiv)
OMe
N3
MeO
4.3
386 76% + 405 54%
(b)
O
+
DMF (0.1 M), 60 °C
under O2 (1 atm)
Ph
407 9%
Scheme 30
N2
CO2
H–R2
(R2 = alkoxy)
N
R2
HO
O
V
R2
R1
[CuII]
O
H+
[CuII]
O
IV
N
O
R1
[CuIII]
N
R1
C N
Copper(II)-Catalyzed Aerobic Synthesis of
Azaspirocyclohexadienones
To further broaden the substrate scope of the above-mentioned Cu(II)-catalyzed aerobic carbonitrile formation,
the reactions of a-azido amides were tested. The morpholine-derived amide 408 provided the corresponding carbonitrile product, 2-naphthonitrile (382), in good yield
(Scheme 33), although a longer reaction time (36 h) was
required compared with that for the synthesis from esters
(see Scheme 27).
N3
N2
R2
O
R1
O
III
O
O
R2
R2
R1
O
R2
H
O
I
408
O Cu(OAc)2 (20 mol%)
K2CO3 (1 equiv)
DMF, 60 °C
under O2 (1 atm)
36 h
[Cu]
N
CN
R
Ar
O
382 73%
Scheme 33
N2, H +
O
II
Scheme 31
Based on these results, a mechanism for this aerobic
Cu(OAc)2-catalyzed carbonitrile formation was proposed,
as shown in Scheme 31. In this possible mechanism, iminylcopper intermediate II is formed from the a-azido carSynlett 2012, 23, 21–44
N
[CuII]
[CuII]
N
O2
III
Scheme 32
O (18O)
405 63%
386 81%
Cu(OAc)2 (20 mol%)
K2CO3 (1 equiv)
O
HO
+
Ph
406
(1 equiv)
O
(a)
IV
R2
O
R2
R1
OMe
O
R1–CN
N
CN
404 +
O
[CuIII]O
path b
DMF (0.1 M), 60 °C
under O2 (18O2) (1 atm)
O
404
MeO
O2
N-Phenyl-substituted amide 409 was next subjected to 20
mol% of Cu(OAc)2 in the presence of potassium phosphate at 80 °C under an oxygen atmosphere to confirm the
co-product after the expected carbon–carbon bond cleavage (i.e., N-methylaniline) (Scheme 34).68 In this case, the
reaction was complete within 4 hours and, surprisingly,
azaspirocyclohexadienone 410 was isolated in 77% yield
without any observation of the carbon–carbon bond cleav-
© Thieme Stuttgart · New York
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40
ACCOUNT
age. The use of 18O2 revealed that one of the oxygen atoms
from molecular oxygen is installed in the resulting carbonyl group of azaspirodienone 410. The reaction with 1
equivalent of Cu(OAc)2 under an argon atmosphere exclusively provided a-keto amide 411, which was formed
via hydrolysis of the corresponding iminylcopper species
or N-H imine.
Table 20 Copper(II) Acetate Catalyzed Synthesis of Azaspirocyclohexadienonesa,b
O
N2
N
R3
N
R1
O
Cu(OAc)2 (20 mol%)
K3PO4 (1 equiv)
R3
N
R2
DMF, 80 °C
under O2 (1 atm)
O
MeO
O
Cu(OAc)2 (20 mol%)
K3PO4 (1 equiv)
N
N
O
O
DMF, 80 °C, 4 h
under O2 (18O2)
(1 atm)
Cu(OAc)2 (100 mol%)
K3PO4 (1 equiv)
NMe
O
O
N
409
DMF, 80 °C, 4 h
under Ar
OMe
N
N
N
NMe
NPh
NMe
NMe
Ph
Ph
Ph
O
O
1
O
O
412: R = 3,5-Me2C6H3; 78%
426: 77%
425: 60%
424: 60%
413: R1 = 4-PhC6H4; 75%
414: R1 = 2-naphthyl; 83%
O
O
1
c
Me
415: R = 1-naphthyl; 55%
Me
416: R1 = 4-MeOC6H4; 65%d
Me
Me
1
417: R = 4-ClC6H4; 81%
1
N
N
418: R = 4-BrC6H4; 80%
NMe
N
419: R1 = 3,5-F2C6H3; 76%
Ph
Ph
Ph
1
420: R = 3,5-(F3C)2C6H3; 65%
O
O
421: R1 = 4-NCC6H4; 69%
428: 72%
427: 75%
422: R1 = 1-adamantyl; 29%e
423: R1 = Me; 0%e,f
R1
410 77%
409
O
O
MeO
N
N
Me
N-R2
R1
O (18O)
N2
41
Applications of Organic Azides for the Synthesis of Nitrogen-Containing Molecules
Me
O
411 68%
The spirodienone structures have commonly been constructed by the oxidative treatment of phenol derivatives.69,70 This unprecedented and mechanistically
intriguing formation of azaspirodienones, as well as the
potential pharmaceutical properties of their derivatives,71
drove us to explore the substrate scope of our reaction
(Table 20).68 By varying substituent R1, aryl rings bearing
various groups (regardless of their electronic nature)
could be introduced, as in the formation of 412–421. This
process could also keep carbon–halogen bonds intact,
such as those in the reactions to give 417–420. Alkyl
groups as R1, such as those in 422 and 423, were not viable for this transformation. Azaspirodienones 424, 425,
427, and 428 bearing electron-donating substituents on
the cyclohexadienone ring were formed in good yields. In
addition to methyl as substituent R2 on the amide nitrogen,
phenyl and benzyl groups could be used, such as in the
synthesis of 426 and 428, respectively.
During the course of this study, the reactions of certain
substrates gave significant mechanistic information. The
reaction of azide 429, sterically hindered by a 2,6-dimethylphenyl group, afforded azaspirodienone 430 in 25%
yield along with N-phenylimine 431 in 36% yield
(Scheme 35, part a). The latter compound could be
formed by the transfer of the phenyl group from the amide
nitrogen to the imine nitrogen via an intramolecular ipsosubstitution reaction of the corresponding iminylcopper.
Interestingly, the treatment of N-4-tolyl amide derivative
432 under the catalytic conditions afforded diastereomers
of azaspirocyclohexadienol 433 and demethylated azaspirodienone 410 in 42 and 6% yield, respectively, without the formation of expected spirocyclohexa-2,4-dienone
434 (Scheme 35, part b).
Based on these results, a mechanistic pathway was proposed, as depicted in Scheme 36. In this mechanism, the
denitrogenative formation of iminylcopper II via deproto© Thieme Stuttgart · New York
a
The reactions were carried out using 0.5 mmol of the a-azido amide
with 20 mol% of Cu(OAc)2 and 1 equiv of K3PO4 in DMF (0.1 M) at
80 °C under an O2 atmosphere.
b
Isolated yields are shown next to the corresponding products.
c
1-Naphthonitrile and N-methylaniline were also obtained in 21 and
19% yield, respectively.
d
4-Methoxybenzonitrile and N-methylaniline were also obtained in
27 and 12% yield, respectively.
e
NaOMe (1 equiv) was used as a base.
f
N-Methylaniline was obtained in 45% yield.
nation of I occurs, which is followed by the oxidation of
II with molecular oxygen to form peroxycopper(III) III.
The formation of azaspirocyclohexadienol in the reaction
of N-4-tolylamide 432 (Scheme 35, part b) indicates that
the intramolecular imino-cupration of III might occur to
form carbon–nitrogen and carbon–copper bonds concurrently at the ipso- and para-positions of the benzene ring,
O
N2
Me N
Cu(OAc)2 (20 mol%)
NaOMe (1 equiv)
N
Me
O
Me
429
DMF, 80 °C
under O2 (1 atm)
N
Ar
N
Cu(OAc)2 (20 mol%)
K3PO4 (1 equiv)
N2
N
Ph
N
Me
O
432
H
N
Ar
(a)
Me
O
O
431 36%
430 25%
(Ar = 2,6-dimethylphenyl)
HO
Me
N
+
NMe
Me
Me
+
N
NMe
OH
NMe
Ph
Ph
O
433-(5R*,8R*)
18%
O
433-(5S*,8S*)
24%
DMF, 80 °C
under O2 (1 atm)
(b)
O
Me
+
N
O
N
NMe
Ph
O
410 6%
NMe
Ph
O
434 0%
Scheme 35
Synlett 2012, 23, 21–44
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Scheme 34
42
ACCOUNT
S. Chiba
O
N2
N
N
1
R
N R2
O
base
[Cu(OAc)2 for initiation]
R1
O [CuII]
O H
N
O
[CuII–OH]
VI
N2 [CuII]
N
Ph
N 2
R1
R
H O
I
base
N R2
R1
O
Ph
N 2
R
V
N2, H+•base
O O
[CuIII] H
[CuII]
N
N
R1
IV
O
N R2
O
[CuIII]
O
N
R1
O
R2
II
O2
N
N
R1
O
R2
III
respectively, affording IV. The subsequent isomerization
of IV to give peroxydiene V followed by elimination of
hydroxidocopper(II) species VI72 would form the azaspirodienone. The observed transfer of the phenyl group
shown in Scheme 35, part a, might proceed via carbon–
nitrogen bond cleavage of IV.
5
Conclusion
We have explored the intriguing chemical reactivities of
several organic azides, such as vinyl azides, cyclic 2-azido
alcohols, and a-azido carbonyl compounds, which can
lead to various kinds of synthetic transformations to give
nitrogen-containing molecules. Although there is a general conception that ‘organic azides = 1,3-dipolar cycloaddition (click chemistry)’, organic azides potentially
possess diverse chemical reactivities working as a onenitrogen unit which can be driven by the elimination of
molecular nitrogen.
Acknowledgment
Our co-workers whose names appear in the references are gratefully
acknowledged for their intellectual and experimental contributions.
The work was supported by funding from Nanyang Technological
University, Singapore Ministry of Education (Academic Research
Fund Tier 2: MOE2010-T2-1-009), and the Science and Engineering Research Council (A*STAR grant No. 082 101 0019).
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